NO832801L - METHOD FOR PREPARING BETA-LACTAM ANTIBIOTICS - Google Patents

METHOD FOR PREPARING BETA-LACTAM ANTIBIOTICS

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Publication number
NO832801L
NO832801L NO832801A NO832801A NO832801L NO 832801 L NO832801 L NO 832801L NO 832801 A NO832801 A NO 832801A NO 832801 A NO832801 A NO 832801A NO 832801 L NO832801 L NO 832801L
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Norway
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amino
methyl
oxo
ester
oxy
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NO832801A
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Norwegian (no)
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Hermann Breuer
Henner Straub
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Squibb & Sons Inc
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Publication of NO832801L publication Critical patent/NO832801L/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
    • C07D205/085—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams with a nitrogen atom directly attached in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Oncology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Communicable Diseases (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Cephalosporin Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

Antibiotisk aktive Ø-laktamer med en. substituent i 1-stillingen og en amino-, acylamino- eller eventuelt beskyttet aminosubstituent i 3-stillingen, eller en ester eller et salt derav; hvor Rog Rg er like eller forskjellige og hver står for hydrogen, alkyl, alkenyl, aynyl, fenyl, substituert fenyl, cykloalkyl eller en 4-, 5-, 6- eller 7-leddet heterocyklus, eller Rog Rg sammen med det karbonatom som de er knyttet til, utgjør cykloalkyl eller en 4-, 5-, 6- eller 7-leddet heterocyklus, eller en av Rog Rg er hydrogen og den annen azido, halogenmetyl, dihalogenmetyl, trihalogenmetyl, halogen, alkoksykarbony1, alkenyl, alkynyl, 2-fenyletenyl, 2-fenyletynyl, karboksyl, -CI^-X-S-X, -0-X, eller -A-CO-XgX, hvor X^^ er azido, amino, hydroksy, alkanoylamino, fenylkarbonylamino, (substituert fenyl)karbonyl-amino, alkylsulfonyloksy, fenylsulfonyloksy, (substituert fenyl)-sulfonyloksy, fenyl, substituert fenyl, cyano, -A-CO-NXgX, -S-Xeller -0-X; Xer alkyl, substituert alkyl, fenyl,substituert fenyl, fenylalkyl, (substituert fenyUalkyl, alkanoyl, fenylalkanoyl, (substituert fenyl)alkanoyl, fenyl-karbonyl, (substituert fenyl)karbonyl eller heteroarylkarbony1; A er -C=CH-, -(CH)-, -CH-0-, -CH-NH- eller -CH-S-CH; n er 0, 1 eller 2; og Xg og X? er like eller forskjellige og er hver hydrogen, alkyl, fenyl eller substituert fenyl, eller xer hydrogen og Xer amino, substituert amino, acylamino eller alkoksy, eller Xg og Xsammen med det nitrogenatom som de er knyttet til, danner en 4-, 5-, 6- eller 7-leddet heterocyklus.Fremstilling av forbindelsene er beskrevet.Antibiotically active β-lactams with a. substituent in the 1-position and an amino, acylamino or optionally protected amino substituent in the 3-position, or an ester or a salt thereof; wherein Rog Rg is the same or different and each represents hydrogen, alkyl, alkenyl, aynyl, phenyl, substituted phenyl, cycloalkyl or a 4-, 5-, 6- or 7-membered heterocycle, or Rog Rg together with the carbon atom which they is attached, constitutes cycloalkyl or a 4-, 5-, 6- or 7-membered heterocycle, or one of Rog Rg is hydrogen and the other azido, halomethyl, dihalomethyl, trihalomethyl, halogen, alkoxycarbonyl, alkenyl, alkynyl, 2- phenylethenyl, 2-phenylethynyl, carboxyl, -C 1-4 -XSX, -O-X, or -A-CO-XgX, wherein X alkylsulfonyloxy, phenylsulfonyloxy, (substituted phenyl) -sulfonyloxy, phenyl, substituted phenyl, cyano, -A-CO-NXgX, -S-X or -O-X; X is alkyl, substituted alkyl, phenyl, substituted phenyl, phenylalkyl, (substituted phenylalkyl, alkanoyl, phenylalkanoyl, (substituted phenyl) alkanoyl, phenylcarbonyl, (substituted phenyl) carbonyl or heteroarylcarbonyl; A is -C = CH-, - (CH ) -, -CH-O-, -CH-NH- or -CH-S-CH; n is 0, 1 or 2, and Xg and X 'are the same or different and are each hydrogen, alkyl, phenyl or substituted phenyl , or xer hydrogen and Xer amino, substituted amino, acylamino or alkoxy, or Xg and X together with the nitrogen atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycle. Preparation of the compounds is described.

Description

Foreliggende oppfinnelse angår en ny familie av 3-laktam-antibiotika og deres bruk som antibakterielle midler. Det har vist seg at 3-laktamkjernen kan aktiveres biologisk av en The present invention relates to a new family of 3-lactam antibiotics and their use as antibacterial agents. It has been shown that the 3-lactam core can be biologically activated by a

substituent med formelensubstituent with the formula

(eller, en ester eller salt (or, an ester or salt

derav) knyttet til kjernens nitrogenatom.hence) attached to the core nitrogen atom.

3-laktamer med en3-lactams with a

substituent (eller en ester substituent (or an ester

eller salt derav) i 1-stillingen og en acylaminosubstituent i 3-stillingen, har virkning overfor gram-negative og gram- or salt thereof) in the 1-position and an acylamino substituent in the 3-position, is effective against gram-negative and gram-

positive bakterier.positive bacteria.

Illustrerende representanter for den nye familie av 3-laktamantibiotika ifølge oppfinnelsen er slike som omfattes av formelen: Illustrative representatives of the new family of 3-lactam antibiotics according to the invention are those covered by the formula:

og estere og salter derav. and esters and salts thereof.

De symboler som er benyttet i formel I og i denne be-The symbols used in formula I and in this be-

skrivelse, har følgende betydninger.letter, has the following meanings.

R 1 er acyl eller hydrogen eller en amino- eller nitrogen-R 1 is acyl or hydrogen or an amino or nitrogen

beskyttende gruppe; protective group;

R2er hydrogen eller metoksy; R 2 is hydrogen or methoxy;

R- og R^er like eller forskjellige og er hver hydrogen,R- and R^ are the same or different and are each hydrogen,

alkyl, alkenyl, alkynyl, cykloalkyl, fenyl, substituert fenyl eller en 4-, 5-, 6- eller 7-leddet heterocyklus (i det følgende omtalt som Rx) eller den ene av R^og R^er hydrogen og den annen er azido, halogenmetyl, dihalogenmetyl, trihalogenmetyl, alkoksykarbonyl, 2-fenyletenyl, 2-fenyletynyl, karboksyl, alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, substituted phenyl or a 4-, 5-, 6- or 7-membered heterocycle (hereinafter referred to as Rx) or one of R^ and R^ is hydrogen and the other is azido, halomethyl, dihalomethyl, trihalomethyl, alkoxycarbonyl, 2-phenylethenyl, 2-phenylethynyl, carboxyl,

-CH2X1[hvor er azido, amino (-Nr^)/hydroksy, alkanoylamino, fenylkarbonylamino, (substituert fenyl)karbonylamino, alkyl- -CH2X1[where is azido, amino (-Nr^)/hydroxy, alkanoylamino, phenylcarbonylamino, (substituted phenyl)carbonylamino, alkyl-

sulfonyloksy, fenylsulfonyloksy, (substituert fenyl)sulfonyl-sulfonyloxy, phenylsulfonyloxy, (substituted phenyl)sulfonyl-

oksy, fenyl, substituert fenyl, cyano,oxy, phenyl, substituted phenyl, cyano,

-s-x2, -s-x2,

eller -0-Xo(hvor A, X0, X, og X_ er som nedenfor definert)]or -0-Xo (where A, X0, X, and X_ are as defined below)]

/.Z. b //.Z. b /

-S-X eller _0-X2[hvor X2er alkyl, substituert alkyl, fenyl, substituert fenyl, fenylalkyl, (substituert fenyl)alkyl, alkanoyl, fenylalkanoyl (substituert fenyl)alkanoyl, fenyl-karbonyl, (substituert fenyl)karbonyl eller heteroarylkarbonyl], -S-X or _O-X2[where X2 is alkyl, substituted alkyl, phenyl, substituted phenyl, phenylalkyl, (substituted phenyl)alkyl, alkanoyl, phenylalkanoyl (substituted phenyl)alkanoyl, phenylcarbonyl, (substituted phenyl)carbonyl or heteroarylcarbonyl],

[hvor en av X^og X^er hydrogen og den annen er hydrogen eller alkyl, eller X^og X^sammen med det karbonatom som de er knyttet til danner en cykloalkylgruppe; og X^er formyl, alkanoyl, fenylkarbonyl, (substituert fenyl)karbonyl, fenyl-alkylkarbonyl, (substituert fenyl)alkyl-karbonyl, karboksyl, alkoksykarbonyl, aminokarbonyl [where one of X^ and X^ is hydrogen and the other is hydrogen or alkyl, or X^ and X^ together with the carbon atom to which they are attached form a cycloalkyl group; and X^ is formyl, alkanoyl, phenylcarbonyl, (substituted phenyl)carbonyl, phenylalkylcarbonyl, (substituted phenyl)alkylcarbonyl, carboxyl, alkoxycarbonyl, aminocarbonyl

(substituert amino)- karbonyl eller cyano (-C=N)], eller (substituted amino)- carbonyl or cyano (-C=N)], or

(hvor A er (where A is

-CH=CH-, -(CH2)n-, -CH2-0-, -CH2-NH-, eller CJ^-S-Cr^-, n er 0, 1 eller 2, og og X^er like eller forskjellige og er hver hydrogen, alkyl, fenyl eller substituert fenyl, eller X^ D er hydrogen og X7amino, substituert amino, acylamino eller alkoksy, eller X^ og X^sammen med det nitrogenatom som de er knyttet til danner en 4-, 5-, 6- eller 7-leddet heterocyklus); og -CH=CH-, -(CH2)n-, -CH2-0-, -CH2-NH-, or CJ^-S-Cr^-, n is 0, 1 or 2, and and X^ are equal or different and are each hydrogen, alkyl, phenyl or substituted phenyl, or X^ D is hydrogen and X7amino, substituted amino, acylamino or alkoxy, or X^ and X^ together with the nitrogen atom to which they are attached form a 4-, 5 -, 6- or 7-membered heterocycle); and

R og Rg er like eller forskjellige og er hver hydrogen, alkyl, alkenyl, alkynyl, fenyl, substituert fenyl, cykloalkyl R and Rg are the same or different and are each hydrogen, alkyl, alkenyl, alkynyl, phenyl, substituted phenyl, cycloalkyl

eller R , eller Rcog R, sammen med det karbonatom som de eror R , or R and R , together with the carbon atom that they are

x Db x Db

knyttet til, utgjør cykloalkyl eller R , eller en av R,, og Rfi er hydrogen og den annen azido, halogenmetyl, dihalogenmetyl, trihalogenmetyl, halogen, alkoksykarbonyl, alkenyl, alkynyl, 2-fenyletenyl, 2-fenyletynyl, karboksyl, -CH2~X1, -S-X2, linked to, is cycloalkyl or R , or one of R 1 , and R 1 is hydrogen and the other is azido, halomethyl, dihalomethyl, trihalomethyl, halogen, alkoxycarbonyl, alkenyl, alkynyl, 2-phenylethenyl, 2-phenylethynyl, carboxyl, -CH2~ X1, -S-X2,

-0-X2, eller -0-X2, or

I det følgende er det angitt definisjoner av forskjellige uttrykk, benyttet for beskrivelse av (3-laktamene ifølge oppfinnelsen. Disse gjelder uttrykkene slik de er benyttet i beskrivelsen (om de ikke i bestemte tilfeller har visse begrensninger) enten individuelt eller som del av en større gruppe. In the following, there are definitions of various expressions used to describe the (3-lactams according to the invention. These apply to the expressions as they are used in the description (if they do not in certain cases have certain limitations) either individually or as part of a larger group.

Uttrykket "alkyl" og "alkoksy" viser til både rette grupper og grupper med forgrenede kjeder. Grupper med 1 til 10 karbohatomer er foretrukket. The terms "alkyl" and "alkoxy" refer to both straight and branched chain groups. Groups with 1 to 10 carbon atoms are preferred.

Uttrykket "cykloalkyl" og "cykloalkenyl" viser til cykloalkyl og cykloalkenyl-grupper med 3, 4, 5, 6 eller 7 karbonatomer. The terms "cycloalkyl" and "cycloalkenyl" refer to cycloalkyl and cycloalkenyl groups with 3, 4, 5, 6 or 7 carbon atoms.

Uttrykket "substituert alkyl" viser til alkylgrupper substituert med en eller flere azido, amino (-NH^), halogen, hydroksy, karboksy, cyano, alkoksykarbonyl, aminokarbonyl, alkanoyloksy, alkoksy, fenyloksy, (substituert fenyl)oksy, R - oksy, merkapto, alkyltio, fenyltio, (substituert fenyl)tio, alkylsulfinyl eller alkylsulfonyl-grupper. The term "substituted alkyl" refers to alkyl groups substituted with one or more azido, amino (-NH^), halogen, hydroxy, carboxy, cyano, alkoxycarbonyl, aminocarbonyl, alkanoyloxy, alkoxy, phenyloxy, (substituted phenyl)oxy, R -oxy, mercapto, alkylthio, phenylthio, (substituted phenyl)thio, alkylsulfinyl or alkylsulfonyl groups.

Uttrykkene "alkanoyl", "alkenyl" og "alkynyl" viser til grupper med både rette og forgrenede kjeder. Grupper med 2 til 10 karbonatomer er foretrukket. The terms "alkanoyl", "alkenyl" and "alkynyl" refer to groups with both straight and branched chains. Groups with 2 to 10 carbon atoms are preferred.

Med "halogen" skal forstås fluor, klor, brom og jod. By "halogen" shall be understood fluorine, chlorine, bromine and iodine.

Uttrykket "beskyttet karboksyl" viser til en karboksyl-gruppe som er forestret med en konvensjonell syrebeskyttende gruppe. Slike grupper er vel kjent; se for eksempel US. patent 4.144.333 av 13. mars, 1979. De foretrukne beskyttede karboksylgrupper er benzyl, benzhydryl, t-butyl og p-nitrobenzyl estere. The term "protected carboxyl" refers to a carboxyl group that is esterified with a conventional acid protecting group. Such groups are well known; see for example US. patent 4,144,333 of March 13, 1979. The preferred protected carboxyl groups are benzyl, benzhydryl, t-butyl and p-nitrobenzyl esters.

Uttrykket "substituert fenyl" viser til en fenylgruppe som er substituert med 1, 2 eller 3 amino, (-NH^), halogen, hydroksyl, trifluormetyl, alkyl (med 1 til 4 karbonatomer), alkoksy, (med 1 til 4 karbonatomer) eller karboksylgrupper. The term "substituted phenyl" refers to a phenyl group substituted with 1, 2 or 3 amino, (-NH^), halogen, hydroxyl, trifluoromethyl, alkyl (of 1 to 4 carbon atoms), alkoxy, (of 1 to 4 carbon atoms) or carboxyl groups.

Uttrykket "en 4-, 5-, 6- eller 7-leddet heterocyklus" The term "a 4-, 5-, 6- or 7-membered heterocycle"

(omtalt som "R x") viser til substituerte og usubstituerte aromatiske og ikke-aromatiske grupper som inneholder ett eller flere nitrogen, oksygen eller svovel-atomer. Som substituenter kan eksempelvis nevnes okso (=0), halogen, hydroksy, nitro, amino, cyano, trifluormetyl, alkyl med 1 til 4 karbonatomer, alkoksy med 1 til 4 karbonatomer, alkylsulfonyl, fenyl, (referred to as "R x ") refers to substituted and unsubstituted aromatic and non-aromatic groups containing one or more nitrogen, oxygen or sulfur atoms. Examples of substituents that can be mentioned are oxo (=0), halogen, hydroxy, nitro, amino, cyano, trifluoromethyl, alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, alkylsulfonyl, phenyl,

substituert fenyl, 2-furfurylidenamino substituted phenyl, 2-furfurylideneamino

benzylidenimino og substituerte alkylgrupper (hvor alkyl- benzylideneimino and substituted alkyl groups (where alkyl-

gruppen har 1 til 4 karbonatomer). En type av "4-, 5-, 6- eller 7-leddet heterocyklus" er "heteroaryl"-gruppen. Uttrykket "heteroaryl" viser til de 4-, 5-, 6- eller 7-leddede heterocykler som er aromatiske. Eksempelvis kan nevnes substituerte og usubstituerte pyridinyl, furanyl, pyrrolyl, tienyl, 1,2,3-triazolyl, 1,2,4-triazolyl, imidazolyl, tiazolyl, tiadiazolyl, pyrimidinyl, oksazolyl, triazinyl og tetrazolyl. Ikke-aromatiske heterocykler (dvs. helt eller delvis mettede heterocykliske grupper) er for eksempel substituert og usubstituert azetinyl, oksetanyl, tietanyl, piperidinyl, piperazinyl, imid-azolidinyl, oksazolidinyl, pyrrolidinyl, tetrahydropyrimidinyl, dihydrotiazolyl og heksahydroazepinyl. Eksempler på substituerte 4-, 5-, 6- eller 7-leddede heterocykler er 1-alkyl-3-azetinyl, 2- okso-1-imidazolidinyl, 3-alkylsulfonyl-2-okso-1-imidazolidinyl, 3- benzylimino-2-okso-1-imidazolidinyl, 3-alkyl-2-okso-1-imidazolidinyl, 3-fenyl (eller substituert fenyl)-2-okso-1-imidazolidinyl, 3-benzyl-2-okso-1-imidazolidinyl, 3-(2-amino-etyl)-2-okso-1-imidazolidinyl, 3-amino-2-okso-1-imidazolidinyl, 3-[(alkoksykarbonyl)amino]-2-okso-1-imidazolidinyl, 3-t2-[(alkoksykarbonyl) -amino]etyl]-2-okso-1-imidazolidinyl, 2-okso-1-pyrrolidinyl, 2-okso-3-oksazolidinyl, 4-hydroksy-6-metyl-2-pyrimidinyl, 2-okso-1-heksahydroazepinyl, 2-okso-3-pyrrolidinyl, 2-okso-3-tetrahydrofuranyl, 2,3-diokso-1-piperazinyl, 2,5-diokso-1-piperazinyl, 4-alkyl-2,3-diokso-1-piperazinyl, og 4-fenyl-2,3-diokso-1-piperazinyl. group has 1 to 4 carbon atoms). One type of "4-, 5-, 6- or 7-membered heterocycle" is the "heteroaryl" group. The term "heteroaryl" refers to the 4-, 5-, 6- or 7-membered heterocycles which are aromatic. For example, substituted and unsubstituted pyridinyl, furanyl, pyrrolyl, thienyl, 1,2,3-triazolyl, 1,2,4-triazolyl, imidazolyl, thiazolyl, thiadiazolyl, pyrimidinyl, oxazolyl, triazinyl and tetrazolyl can be mentioned. Non-aromatic heterocycles (ie fully or partially saturated heterocyclic groups) are, for example, substituted and unsubstituted azetinyl, oxetanyl, thietanyl, piperidinyl, piperazinyl, imido-azolidinyl, oxazolidinyl, pyrrolidinyl, tetrahydropyrimidinyl, dihydrothiazolyl and hexahydroazepinyl. Examples of substituted 4-, 5-, 6- or 7-membered heterocycles are 1-alkyl-3-azetynyl, 2-oxo-1-imidazolidinyl, 3-alkylsulfonyl-2-oxo-1-imidazolidinyl, 3-benzylimino-2 -oxo-1-imidazolidinyl, 3-alkyl-2-oxo-1-imidazolidinyl, 3-phenyl (or substituted phenyl)-2-oxo-1-imidazolidinyl, 3-benzyl-2-oxo-1-imidazolidinyl, 3- (2-Amino-ethyl)-2-oxo-1-imidazolidinyl, 3-amino-2-oxo-1-imidazolidinyl, 3-[(Alkoxycarbonyl)amino]-2-oxo-1-imidazolidinyl, 3-t2-[ (Alkoxycarbonyl)-amino]ethyl]-2-oxo-1-imidazolidinyl, 2-oxo-1-pyrrolidinyl, 2-oxo-3-oxazolidinyl, 4-hydroxy-6-methyl-2-pyrimidinyl, 2-oxo-1 -hexahydroazepinyl, 2-oxo-3-pyrrolidinyl, 2-oxo-3-tetrahydrofuranyl, 2,3-dioxo-1-piperazinyl, 2,5-dioxo-1-piperazinyl, 4-alkyl-2,3-dioxo-1 -piperazinyl, and 4-phenyl-2,3-dioxo-1-piperazinyl.

Uttrykket "substituert amino" viser til en gruppe med formel -NY^Y2hvor Y- er hydrogen, alkyl, fenyl, substituert fenyl, fenylalkyl eller (substituert fenyl)alkyl, og Y^er alkyl, fenyl, substituert fenyl, fenylalkyl, (substituert fenyl)alkyl, hydroksy, cyano, alkoksy, fenylalkoksy eller amino (-NH2). The term "substituted amino" refers to a group of formula -NY^Y2where Y- is hydrogen, alkyl, phenyl, substituted phenyl, phenylalkyl or (substituted phenyl)alkyl, and Y^ is alkyl, phenyl, substituted phenyl, phenylalkyl, (substituted phenyl)alkyl, hydroxy, cyano, alkyloxy, phenylalkyloxy or amino (-NH 2 ).

Uttrykket "acyl" viser til alle organiske radikaler som kan avledes fra en organisk syre (dvs. en karboksylsyre) ved å fjerne hydroksylgruppen. Som eksempel kan nevnes acylgrupper som tidligere er blitt benyttet for å acylere 3~laktam-antibiotika, innbefattet 6-aminopenicillansyre og 7-amino-cefalosporansyre og derivatene av disse; se f.eks. "Cephalo-sporins and Penicillins", redigert av Flynn, Academic Press The term "acyl" refers to any organic radical that can be derived from an organic acid (ie, a carboxylic acid) by removing the hydroxyl group. Examples include acyl groups that have previously been used to acylate 3-lactam antibiotics, including 6-aminopenicillanic acid and 7-amino-cephalosporanic acid and their derivatives; see e.g. "Cephalosporins and Penicillins", edited by Flynn, Academic Press

(1972), tysk utleggingsskrift 2.716.677, av 10. oktober 1978, belgisk patent 867.994, av 11 . desember 1978. US. patent 4.152.432 av 1. mai, 1979, US. patent 3.971.778 av 27. juli, 1976, US.patent 4.172.199 av 23. oktober 1979, og britisk patent 1.348.894 av 27. mars, 1974. Den følgende liste angir eksempler på acylgrupper: (1972), German Publication No. 2,716,677, of October 10, 1978, Belgian Patent 867,994, of 11 . December 1978. US. patent 4,152,432 of May 1, 1979, US. patent 3,971,778 of July 27, 1976, US patent 4,172,199 of October 23, 1979, and British patent 1,348,894 of March 27, 1974. The following list indicates examples of acyl groups:

(a) Alifatiske grupper med formelen:(a) Aliphatic groups of the formula:

hvor R a.er alkyl; cykloalkyl; alkoksy; alkenyl; cykloalkenyl; cykloheksadienyl; eller alkyl eller alkenyl substituert med en eller flere halogen, cyano, nitro, amino, merkapto, alkyltio eller cyanometyltio-grupper. where R a. is alkyl; cycloalkyl; alkoxy; alkenyl; cycloalkenyl; cyclohexadienyl; or alkyl or alkenyl substituted with one or more halogen, cyano, nitro, amino, mercapto, alkylthio or cyanomethylthio groups.

(b) Karbocykliske aromatiske grupper med formelen:(b) Carbocyclic aromatic groups of the formula:

hvor n er 0, 1, 2 eller 3; R^, Rcog R^uavhengig av hverandre står for hydrogen, halogen, hydroksy1, nitro, amino, cyano, trifluormetyl, alkyl med 1 til 4 karbonatomer, alkoksy med 1 til 4 karbonatomer eller aminometyl; og Rg er amino, hydroksyl, et karboksylsalt, beskyttet karboksyl, formyloksy, et sulfosalt, et sulfaminosalt, azido, halogen, hydrazino, alkylhydrazino, fenylhydrazino eller [(alkyltio)tioksymetyl]tio. where n is 0, 1, 2 or 3; R₁, R₂ and R₂ independently of each other represent hydrogen, halogen, hydroxy, nitro, amino, cyano, trifluoromethyl, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or aminomethyl; and Rg is amino, hydroxyl, a carboxyl salt, protected carboxyl, formyloxy, a sulfosalt, a sulfaminosalt, azido, halogen, hydrazino, alkylhydrazino, phenylhydrazino, or [(alkylthio)thiooxymethyl]thio.

Foretrukne karbocykliske aromatiske acylgrupper innbefatter de med formelen: Preferred carbocyclic aromatic acyl groups include those of the formula:

(Rg er fortrinnsvis et karboksylsalt eller et sulfosalt) og (R er fortrinnsvis et karboksylsalt eller et sulfosalt). (c) Heteroaromatiske grupper med formelen: (Rg is preferably a carboxyl salt or a sulfosalt) and (R is preferably a carboxyl salt or a sulfosalt). (c) Heteroaromatic groups of the formula:

hvor n er 0, 1, 2 eller 3; R er som angitt ovenfor og R,, er en e r substituert eller usubstituert 5-, 6- eller 7-leddet hetero-cyklisk ring som inneholder 1, 2, 3 eller 4 (fortrinnsvis 1 eller 2) nitrogen, oksygen og svovel-atomer. Eksempler på heterocykliske ringer er tienyl, furyl, pyrrolyl, pyridinyl, pyrazolyl, pyrazinyl, tiazolyl, pyrimidinyl, tiadiazolyl og tetrazolyl. Substituenter er for eksempel halogen, hydroksyl, nitro, amino, beskyttet amino, cyano, trifluormetyl, alkyl med 1 til 4 karbonatomer, alkoksy med 1 til 4 karbonatomer eller where n is 0, 1, 2 or 3; R is as indicated above and R 1 is a is substituted or unsubstituted 5-, 6- or 7-membered heterocyclic ring containing 1, 2, 3 or 4 (preferably 1 or 2) nitrogen, oxygen and sulfur atoms. Examples of heterocyclic rings are thienyl, furyl, pyrrolyl, pyridinyl, pyrazolyl, pyrazinyl, thiazolyl, pyrimidinyl, thiadiazolyl and tetrazolyl. Substituents are, for example, halogen, hydroxyl, nitro, amino, protected amino, cyano, trifluoromethyl, alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms or

Foretrukne heteroaromatiske acylgrupper innbefatter de med de ovenfor angitte formler hvor R^ er 2-amino-4-tiazolyl, 2-amino-5-halogen-4-tiazolyl, 4-aminopyrimidin-2-yl, 5-amino-1,2,4-tiadiazol-3-yl, 2-tienyl, 2-furanyl eller 6-aminopyridin-2-yl. (d) [[(4-substituert-2,3-diokso-1-piperazinyl)karbonyl]~amino]arylacetyl-grupper med formelen: Preferred heteroaromatic acyl groups include those of the above formulas where R 1 is 2-amino-4-thiazolyl, 2-amino-5-halo-4-thiazolyl, 4-aminopyrimidin-2-yl, 5-amino-1,2, 4-thiadiazol-3-yl, 2-thienyl, 2-furanyl or 6-aminopyridin-2-yl. (d) [[(4-substituted-2,3-dioxo-1-piperazinyl)carbonyl]~amino]arylacetyl groups of the formula:

hvor Rg er en aromatisk gruppe (omfattende karbocykliske aromater som: where Rg is an aromatic group (including carbocyclic aromatics such as:

og heteroaromatiske grupper innbefattet innenfor definisjonen av R^); og R^er alkyl, substituert alkyl (hvor alkyldelen er substituert med en eller flere halogen, cyano, nitro, amino and heteroaromatic groups included within the definition of R 1 ); and R^ is alkyl, substituted alkyl (where the alkyl part is substituted with one or more halogen, cyano, nitro, amino

eller merkapto-grupper), arylmetylenamino (dvs. -N=CH-R 9 hvor or mercapto groups), arylmethyleneamino (ie -N=CH-R 9 where

Rg er som ovenfor angitt), arylkarbonylamino (dvs. Rg is as above), arylcarbonylamino (i.e.

hvor where

Rg er som ovenfor angitt) eller alkylkarbonylamino. Rg is as above) or alkylcarbonylamino.

Foretrukne [[(4-substituert-2,3-diokso-1-piperazinyl)-karbonyl]amino]arylacetyl-grupper innbefatter de hvor R^er etyl, fenylmetylenamino eller 2-furylmetylenamino. Preferred [[(4-substituted-2,3-dioxo-1-piperazinyl)-carbonyl]amino]arylacetyl groups include those where R 1 is ethyl, phenylmethyleneamino or 2-furylmethyleneamino.

(e) (Substituerte oksyimino)arylacetylgrupper med formelen: (e) (Substituted oxyimino)arylacetyl groups of the formula:

hvor R er som ovenfor angitt og R. er hydrogen, alkyl, cyklo-g i where R is as stated above and R. is hydrogen, alkyl, cyclo-g i

alkyl, alkylaminokarbonyl, arylaminokarbonylalkyl, alkylaminocarbonyl, arylaminocarbonyl

(dvs. (ie

hvor R ger som ovenfor angitt) eller substituert where R gives as above) or substituted

alkyl (hvor alkylgruppen er substituert med en eller flere halogen, cyano, nitro, merkapto, alkyltio, aromatisk gruppe (som definert for R ), karboksyl (inkludert salter derav), amido, alkoksykarbonyl, fenylmetoksykarbonyl, difenyl-metoksykarbonyl, hydroksyalkoksyfosfinyl, dihydroksyfosfinyl, hydroksy(fenylmetoksy)fosfinyl eller dialkoksyfosfinyl-substituenter). alkyl (where the alkyl group is substituted by one or more halogen, cyano, nitro, mercapto, alkylthio, aromatic group (as defined for R ), carboxyl (including salts thereof), amido, alkoxycarbonyl, phenylmethoxycarbonyl, diphenyl-methoxycarbonyl, hydroxyalkylphosphinyl, dihydroxyphosphinyl, hydroxy(phenylmethoxy)phosphinyl or dialkoxyphosphinyl substituents).

Foretrukne (substituerte oksyimino)arylacetylgrupper innbefatter slike hvor Rg er 2-amino-4-tiazolyl. Grupper hvor R^er metyl, etyl, karboksymetyl, 1-karboksy-1-metyletyl, 2,2,2-trifluoretyl eller 1-karboksycyklopropyl er også foretrukket, Preferred (substituted oxyimino)arylacetyl groups include those where Rg is 2-amino-4-thiazolyl. Groups where R^ is methyl, ethyl, carboxymethyl, 1-carboxy-1-methylethyl, 2,2,2-trifluoroethyl or 1-carboxycyclopropyl are also preferred,

(f) (acylamino)arylacetylgrupper med formelen: (f) (acylamino)arylacetyl groups of the formula:

hvor R er som ovenfor angitt oq R. er g D amino, alkylamino, (cyanoalkyl)amino, amido, alkylamido, (cyanoalkyl)amido, where R is as stated above and R. is g D amino, alkylamino, (cyanoalkyl)amino, amido, alkylamido, (cyanoalkyl)amido,

Foretrukne (acylamino)arylacetylgrupper med den ovenfor angitte formel, innbefatter slike hvor R., er amino eller amido-grupper. Grupper hvor R^ er fenyl eller 2-tienyl er også foretrukket . (g) [[[3-substituert-2-okso-1-imidazolidinyl]karbonyl]-amino]arylacetylgrupper med formelen: Preferred (acylamino)arylacetyl groups of the above formula include those where R. is amino or amido groups. Groups where R 1 is phenyl or 2-thienyl are also preferred. (g) [[[3-substituted-2-oxo-1-imidazolidinyl]carbonyl]-amino]arylacetyl groups of the formula:

hvor R g er som ovenfor angitt og R, K er hydrogen, alkylsulfonyl, arylmetylenamino (dvs. -N=CH-R , hvor R er som ovenfor angitt), 9 where R g is as above and R, K are hydrogen, alkylsulfonyl, arylmethyleneamino (ie -N=CH-R , where R is as above), 9

(hvor Rmer hydrogen, alkyl eller halogensubstituert (where R is hydrogen, alkyl or halogen substituted

alkyl), en aromatisk gruppe (som angitt ovenfor for R ), alkyl eller substituert alkyl (hvor alkylgruppen er substituert med en eller flere halogen, cyano, nitro, amino eller merkapto-grupper). alkyl), an aromatic group (as indicated above for R ), alkyl or substituted alkyl (where the alkyl group is substituted with one or more halogen, cyano, nitro, amino or mercapto groups).

Foretrukne [[3-substituert-2-okso-1-imidazolidinyl}-karbonyl]amino]arylacetylgrupper med den ovenfor angitte formel innbefatter de hvor R^ er fenyl eller 2-tienyl. Grupper hvor R^er hydrogen, metylsulfonyl, fenylmetylenamino eller 2-furylmetylenamino, er også foretrukket. Preferred [[3-substituted-2-oxo-1-imidazolidinyl}carbonyl]amino]arylacetyl groups of the above formula include those wherein R 1 is phenyl or 2-thienyl. Groups where R 1 is hydrogen, methylsulfonyl, phenylmethyleneamino or 2-furylmethyleneamino are also preferred.

Uttrykkene "salt" og "salter" viser til basiske salter The terms "salt" and "salts" refer to basic salts

dannet med uorganiske og organiske baser. De omfatter ammonium-salter, alkalimetallsalter som natrium- og kaliumsalter (som er foretrukket), jordalkalimetallsalter som kalsium- og magnesium-salter, salter med organiske baser, f.eks. dicykloheksylamin, formed with inorganic and organic bases. They include ammonium salts, alkali metal salts such as sodium and potassium salts (which are preferred), alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases, e.g. dicyclohexylamine,

benzatin, N-metyl-D-glukamin, hydrabamin, og salter med amino-syrer som arginin, lysin og lignende. Ugiftige, farmasøytisk akseptable salter foretrekkes, men andre salter kan også være nyttige, f.eks. ved isolering og rensing av produktet. benzathine, N-methyl-D-glucamine, hydrabamine, and salts with amino acids such as arginine, lysine and the like. Non-toxic, pharmaceutically acceptable salts are preferred, but other salts may also be useful, e.g. when isolating and cleaning the product.

Saltene fremstilles på konvensjonell måte ved å omsette produktets fri syreform med en eller flere ekvivalenter av den passende base, slik at det ønskede kation foreligger i et løsningsmiddel eller medium hvor saltet er uløselig, eller i vann som deretter fjernes ved frysetørking. Ved å nøytralisere resin i hydrogenform (f.eks. polystyrensulfonsyre som Dowex 50) eller med en vandig syre og ekstraksjon med et organisk løsningsmiddel, f.eks. etylacetat, diklormetan eller lignende, kan den fri syreform oppnås og eventuelt omdannes til en annen saltform. The salts are prepared in a conventional manner by reacting the product's free acid form with one or more equivalents of the appropriate base, so that the desired cation is present in a solvent or medium where the salt is insoluble, or in water which is then removed by freeze-drying. By neutralizing resin in hydrogen form (e.g. polystyrene sulphonic acid such as Dowex 50) or with an aqueous acid and extraction with an organic solvent, e.g. ethyl acetate, dichloromethane or the like, the free acid form can be obtained and possibly converted into another salt form.

I denne beskrivelse ansees.ft-laktamer som i 1-stillingen In this description, ft-lactams are considered as in the 1-position

har en ester av gruppen has an ester of the group

som en del av oppfinnelsen. Slike estere er for eksempel alkyl, alkenyl, alkynyl, cykloalkyl, (cykloalkyl)alkyl, R -alkyl, trialkylsilylalkyl, mono-di- eller trihalogen-alkyl, hydroksyalkyl, alkoksyalkyl, karboksyalkyl, alkoksykarbonylalkyl, difenylmetoksykarbonyl-alkyl, karbamoylalkyl, alkylkarbamoylalkyl, dialkylkarbamoyl-alkyl, indanyl, fenyl, substituert fenyl, fenylalkyl, (substituert fenyl)alkyl, Rx~karbonylalkyl, [hvor Y, er hydrogen, alkyl eller fenyl ogY^er hydrogen, alkyl, cykloalkyl, (cykloalkyl)oksy, fenyl eller alkoksy, eller hvor Y^ og Y^tilsammen utgjør -(CH2)2-, -(CH )3-, -CH=CH-, eller as part of the invention. Such esters are, for example, alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, R -alkyl, trialkylsilylalkyl, mono-di- or trihaloalkyl, hydroxyalkyl, alkoxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, diphenylmethoxycarbonylalkyl, carbamoylalkyl, alkylcarbamoylalkyl, dialkylcarbamoyl -alkyl, indanyl, phenyl, substituted phenyl, phenylalkyl, (substituted phenyl)alkyl, Rx~carbonylalkyl, [where Y, is hydrogen, alkyl or phenyl and Y^ is hydrogen, alkyl, cycloalkyl, (cycloalkyl)oxy, phenyl or alkoxy, or where Y^ and Y^ together constitute -(CH2)2-, -(CH )3-, -CH=CH-, or

estere. esters.

Med hydrolyserbare estere forstås estere som kan hydrolyseres in vivo til moder-karboksylsyren og som oppviser den antibiotiske aktivitet av sistnevnte. Ikke-hydrolyserbare estere (estere som ikke hydrolyseres in vivo til moder-karboksylsyren) kan være aktuelle som mellomprodukter, og noen av disse er også virksomme som antibiotika. By hydrolyzable esters are meant esters which can be hydrolysed in vivo to the parent carboxylic acid and which exhibit the antibiotic activity of the latter. Non-hydrolysable esters (esters that are not hydrolysed in vivo to the parent carboxylic acid) may be relevant as intermediates, and some of these are also effective as antibiotics.

3-laktamer med en 3-lactams with a

substituent (eller en ester substituent (or an ester

eller salt derav) i 1-stillingen og en amino- eller acylaminosubstituent i 3-stillingen inneholder minst ett chiralt sentrum, nemlig karbonatomet (i 3-laktamkjernens 3-stilling) som amino-eller acylamino-substituenten er knyttet til. Foreliggende oppfinnelse er rettet mot de ovenfor beskrevne 3-laktamer hvor de or salt thereof) in the 1-position and an amino or acylamino substituent in the 3-position contains at least one chiral center, namely the carbon atom (in the 3-position of the 3-lactam nucleus) to which the amino or acylamino substituent is attached. The present invention is aimed at the above-described 3-lactams where they

stereokjemiske forhold i det chirale senter i 3-stillingen av 3-laktamkjernen er lik konfigurasjonen av karbonatomet i 6-stillingen i naturlig forekommende penicilliner (f.eks. penicillin G), og lik konfigurasjonen av karbonatomet i 7-stillingen av naturlig forekommende cefamyciner, (f.eks. cefamycin C). stereochemical relationship of the chiral center in the 3-position of the 3-lactam core is similar to the configuration of the carbon atom in the 6-position of naturally occurring penicillins (e.g. penicillin G), and similar to the configuration of the carbon atom in the 7-position of naturally occurring cefamycins, (eg cefamycin C).

Når det gjelder de foretrukne 3-laktamer med formel I, er strukturformlene tegnet slik at de viser de stereokjemiske forhold ved det chirale sentrum i 3-stillingen. Som følge av nomenklatur-konvensjonen, har forbindelser med formel I hvor 1*2 er hydrogen, S-konfigurasjonen og forbindelser med formel I hvor R- er metoks,y, R-konfigurasjonen. ;Oppfinnelsen omfatter også racemiske blandinger som inneholder de ovenfor beskrevne 3-laktamer. ;3-laktamer med en ; (eller en ester eller salt derav) i 3-laktamkjernens 1-stilling og en acylaminosubstituent i 3-stillingen, har effekt overfor en rekke gram-negative og gram-positive organismer. ; (eller en ester eller salt derav) er ;vesentlig for disse forbindelsers aktivitet.;Forbindelsene ifølge oppfinnelsen kan benyttes som midler til bekjempelse av bakterielle infeksjoner (innbefattet infeksjoner i urinveier og åndedrettsorganer) i pattedyr som husdyr,(f.eks. hunder, katter, kveg, hester og lignende) og mennesker. ;For bekjempelse av bakterielle infeksjoner gis forbindelsene i mengder på 1,4-350 mg/kg/dag, fortrinnsvis 14-100 mg/kg/dag. Alle administrasjonsmåter som hittil er blitt benyttet for å tilføre penicilliner og cefalosporiner til infeksjonsstedet, kommer også i betraktning for den nye 3~laktamfamilie. Disse innbefatter peroral, intravenøs, intra-muskulær og suppositorie administrasjon. ;3-laktamene ifølge oppfinnelsen kan fremstilles ved å gå ut fra en aminosyre med formelen: ; ; Hvis er hydrogen, blir aminogruppen først beskyttet med en av de klassiske beskyttelsesgrupper (f.eks. t-butoksykarbonyl, benzyloksykarbonyl, o-nitrofenylsulfenyl, etc), hvorved det oppnås en forbindelse med formel: ; hvor betyr en amino- eller nitrogen-beskyttende gruppe.;I formel III, og forøvrig i denne beskrivelse, viser ;symbolet " A^" til en nitrogen- eller amino-beskyttende gruppe. For enkelte produkter med formel I, kan den ønskede acylgruppe "R^" benyttes som den beskyttende gruppe "A^" og således føres inn ved starten av reaksjonsfølgen. ;Karboksylgruppen i en beskyttet aminosyre med formel III eller den korresponderende forbindelse hvor R^er acyl, omsettes deretter med et amin med formel: ; I formel IV, og i beskrivelsen forøvrig, viser symbolet "Y" bl.a. til benzyl, trityl, pivaloyl, -CH2CH(NHA2)C02alkyl, t-butyl, p-nitrobenzyl, benzhydryl, 2-cyanoetyl, 2-trimetyl-silyletyl, trikloretyl og p-anisyl (hvor symbolet "A2" viser til en nitrogen-beskyttende gruppe). Reaksjonen foregår i nærvær av et koblingsmiddel så som l-etyl-3-(3-dimetylamino-propyl)karbodiimid eller dicykloheksylkarbodiimid og fører til en forbindelse med formel: ; Hydroksylgruppen i en forbindelse med formel V omdannes til en utgående gruppe, f.eks. ved bruk av et klassisk reagens som metansulfonylklorid (metansulfonyl omtales i det følgende som "Ms"). ;Den helt beskyttede forbindelse med formel:; cykliseres ved behandling med en base, f.eks. kaliumkarbonat. Reaksjonen utføres fortrinnsvis i et organisk løsningsmiddel som aceton, under tilbakeløpsbetingelser og leder til en forbindelse med formel VII: ; Alternativt kan cyklisering av en forbindelse med formel V oppnås uten først å omdanne hydroksylgruppen til en utgående gruppe. Behandling av en forbindelse med formel V med trifenylfosfin og dietylazodikarboksylat eller karbontetraklorid fører til en forbindelse med formel VII. ;Begge disse ringslutnings-metoder for forbindelse V, fører til inversjon av de stereokjemiske forhold i R^ og R^-substituentene. ;Ved selektiv reduksjon av en forbindelse med formel VII (ved katalytisk hydrogenering hvis Y er benzyl eller ved behandling med en base som natriumsulfid eller natrium-hydroksyd dersom Y er pivaloyl eller med DB.U dersom Y er ;-CH^CH(NHA2)C02alkyl oppnås den korresponderende forbindelse med formel: ; Alkylering av en hydroksamsyre med formel VIII med en aktivert og eventuelt beskyttet form av en forbindelse med formelen: ; kan oppnås ved først å frembringe anionet av hydroksamsyren ved hjelp av en passende base og deretter omsette den resulterende forbindelse med en aktivert form av et eddiksyrederivat med formel IX. Aktiverte og beskyttede former av forbindelse IX har formelen: hvor Yj. er en egnet utgående gruppe, så som et halogenatom (fortrinnsvis brom eller klor), en mesylat- eller triflat-gruppe eller en av de andre velkjente utgående grupper, og Y^er hydrogen eller en estergruppe. Alkyleringen er her beskrevet som en 2-trinns reaksjon, men begge trinn kan utføres samtidig. Det resulterende produkt har formelen: ; Avspaltning av beskyttelsesgruppen fra 3-aminosubstituenten i en forbindelse med formel X kan oppnås ved kjent teknikk. Er den beskyttende gruppe for eksempel t-butoksykarbonyl, kan aminogruppen frigjøres ved hjelp av trifluoreddiksyre. Er beskyttelsesgruppen benzyloksykarbonyl, kan katalytisk (f.eks. palladium-på-karbon) hydrogenering anvendes. Er beskyttelsesgruppen o-nitrofenylsulfenyl, kan en kombinasjon av p-toluen-sulfonsyre og p-tiokresol benyttes. Forbindelsen har etter fjerning av beskyttelsesgruppen formelen: ; og dette mellomprodukt spiller en nøkkelrolle ved fremstilling av forbindelsene i henhold til oppfinnelsen, og utgjør også en del av denne. ;Velkjente acyleringsteknikker kan benyttes for å omdanne en forbindelse med formel XI til den korresponderende forbindelse med formel: ; hvor er acyl. Eksempelvis innbefatter denne teknikk ;omsetning med en karboksylsyre (R^-OH) eller et korresponderende karboksylsyrehalogenid eller karboksylsyreanhydrid. Reaksjonene med en karboksylsyre går lettest i nærvær av et karbodiimid så som dicykloheksylkarbodiimid og en forbindelse som har evne til å danne et reaktivt mellomprodukt in situ, f.eks. N-hydroksybenzotriazol eller N-hydroksysuccinimid. I de tilfelle hvor acylgruppen (R^) inneholder reaktive (f.eks. amino- eller karboksyl-) grupper kan det være nødvendig at disse funksjonlle grupper først beskyttes, hvorpå acyleringsreaksjonen gjennom-føres og det resulterende produkt tilslutt befris for beskyttelsesgruppen. ;Avspalting av den beskyttende gruppe fra karboksylsyren, etterfulgt av eventuell forestring, fører til det ønskede produkt med formel I. Forestringsmetoder er illustrert i eksempelene. ;Det eksisterer alternative metoder for å omdanne et mellomprodukt med formel X til et produkt med formel I. Eksempelvis kan en forbindelse med formel X omsettes med N-metyl-N-trimetylsilyl-trifluoracetamid (MSTFA) og et silan, ;som f.eks. jodtrimetylsilan, for å avspalte "AI " og "Y D"-gruppene og gi den korresponderende 3-trimetylsilylamino-forbindelse som kan acyleres etter de ovenfor beskrevne fremgangsmåter . ;Produktene med formel I, hvor R er metoksy, kan også fremstilles fra den korresponderende forbindelse med formel VII hvor R2er hydrogen. Halogenering (fortrinnsvis klorering) av amidnitrogenet i en forbindelse med formel VII, fører til en forbindelse med formel: ; Reagenser og fremgangsmåter for N-klorering av amider er kjent. Egnede reagenser er for eksempel tert-butylhypokloritt, natriumhypokloritt og klor. Reaksjonen kan utføres i et organisk løsningsmiddel (f.eks. en lavere alkanol som metanol) eller i et tofase-system (f.eks. vann/metylenklorid) i nærvær av en base som natriumborat-dekahydrat, fortrinnsvis ved redusert temperatur. ;Omsetning av en forbindelse med formel XIII med et met-oksyleringsmiddel, f.eks. et alkalimetall-metoksyd, fører til en forbindelse (i kombinasjon med enantiomerene av denne dersom R^og R^er like, eller XIII er en racemisk blanding) med formelen: ; Reaksjonen kan foretas i et organisk løsningsmiddel, f.eks. et. polart organisk løsningsmiddel så som tetrahydrofuran, ved redusert temperatur. ;Som et alternativ kan en forbindelse med formel VII omdannes til forbindelse XIV etter en enkelt-trinns metode. Metoksyleringsmidlet blandes herunder med en forbindelse med formel VII, hvoretter N-kloreringsreagenset tilsettes til reaksjonsblandingen. ;Overføringen av en forbindelse med formel XIV til det ønskede produkt med formel I (eller en ester derav) kan oppnås ved hjelp av de ovenfor beskrevne fremgangsmåter for omdanning av et mellomprodukt med formel XIV til et produkt i henhold til oppfinnelsen. ;En alternativ prosess for fremstilling av forbindelsene ifølge oppfinnelsen, omfatter en mer direkte syntese av forbindelsene med formel X. Omsetning av en N-beskyttet aminosyre med formel III med en forbindelse som dannes ved reaksjon mellom en forbindelse med formel IXa og N-hydroksyftalimid, etterfulgt av omsetning med hydrazin, fører til en forbindelse med formel XV: ; Ved å følge de ovenfor beskrevne fremgangsmåter, kan hydroksylgruppen i en forbindelse med formel XV omdannes til en utgående gruppe og den resulterende forbindelse cykliseres til den korresponderende forbindelse X. ;Utgangsmaterialene med formel II kan lett oppnås etter allerede kjente metoder; se f.eks. Synthesis, s. 216 (1979) og J. Org. Chem., 44:3967 (1979). ;De etterfølgende tabeller viser forbindelser i henhold til oppfinnelsen fremstillet ved hjelp av den ovenfor beskrevne teknikk. Metodikken er ytterligere illustrert for spesifikke forbindelser i de eksempler som følger tabellene. ;I forbindelsene vist i tabellene har oksimene den stereokjemiske syn-form. ; ; Eksempel 1 ;[3S(Z)]-[t 3-[[(2-amino-4-tiazolyl) (metoksyimino)-acetyl]-amino]-2-okso-1-azetidinyl]oksy]eddiksyre-1,1-dimetyletyl- ;ester;A) 0-(t-butyloksykarbonylmetyl)-a-N-(benzyloksykarbonyl)-L-serin- hydroksamat ;En løsning av dicykloheksylkarbodiimid (57,5 g, 0,28 mol);i tørr tetrahydrofuran (60 ml) ble dryppet inn i en løsning av N-a-(benzyloksykarbonyl-L-serin (66,9 g, 0,28 mol), 1-hydroksybenzotriazol-hydrat (42,0 g, 0,28 mol) og t-butylaminoksyacetat (41,2 g, 0,28 mol) i tørr tetrahydrofuran (1,4 liter) ;ved 0-5°C. Blandingen ble omrørt over natten ved romtemperatur. Presipitatet (dicykloheksylurea) ble fjernet ved filtrering og filtratet inndampet under vakuum. Residuet ble løst i etylacetat, vasket med 5% NaHCO^ og med vann. Tørking over MgSO^, etterfulgt av filtrering og inndamping, førte til en rå olje som gikk over i fast form ved behandling med en iskald blanding av eter og petroleter (1:2); utbytte: 83,6 g, ;smp. 64-68°C.;B) (S)-[[3-[(benzyloksykarbonyl)amino-2-okso-1-azetidinyl]-oksy ] eddiksyre- 1 , 1 - dimetyletyl- ester ;Metode I;Trifenylfosfin (26,2 g, 0,1 mol) ble tilsatt til en;løsning av 0-(t-butoksykarbonylmetyl)-a-N-(benzyloksykarbonyl)-L-serin-hydroksamat (36,8 g, 0,1 mol) i 500 ml tørr acetonitril. En løsning av trietylamin (20,9 ml, 0,15 mol) og karbontetraklorid (9,7 ml, 0,1 mol) i 50 ml tørr acetonitril ble dråpevis tilsatt ved romtemperatur, hvorpå blandingen ble omrørt over natten og inndampet under vakuum. Residuet ble løst i kloroform, vasket med vandig buffer-oppløsning pH 4 (citrat/HCl), tørket over MgS04og filtrert. Løsningsmidlet ble deretter fjernet under redusert trykk og residuet kromatografert på kiselgel med eter/etylacetat (2:1). Omkrystallisering av produktet fra eter/petroleter førte til farveløse krystaller; utbytte 20,6 g, smp. 87-88°C. ;Metode II;Tørr pyridin (4,75 g, 60 mmol)ble tilsatt til en løsning av O-(t-butyloksykarbonylmetyl)-a-N-(benzyloksykarbonyl)-L-serin-hydroksamat (11,05 g, 30 mmol) i 150 ml tørr diklormetan. En løsning av metansulfonylklorid (6,8 g, 60 mmol) i 6 ml diklormetan ble dryppet inn i blandingen ved 0°C. Blandingen ble omrørt over natten ved romtemperatur, heilt over i iskaldt vann og ekstrahert gjentatte ganger med diklormetan. De kombinerte organiske lag ble vasket to ganger med fortynnet HC1, med vann, 5% NaHCO^, igjen med vann og deretter tørket over MgSO^. Etter filtrering og konsentrering under vakuum ble det oppnådd en olje som gikk over i fast form ved omrøring med eter. 9,4 g; smp. 92-94°C. ;Dette produkt sammen med produktet fra en ny omgang (totalt 11,2 g, 26 mmol) i 50 ml tørr aceton, ble under til-bakeløpsbetingelser dryppet inn i en suspensjon av vannfri kaliumkarbonat (21,1 g, 0,15 mol) i 100 ml tørr aceton. Blandingen ble kraftig omrørt og tilbakeløpsbehandlet i ;1,5 timer, deretter avkjølt til romtemperatur, filtrert og inndampet under vakuum. Residuet ble løst i eter, vasket med vann og tørket over MgSO^. Filtrering og konsentrering under vakuum førte til den rå tittelforbindelse som ble omkrystallisert fra eter/petroleter; utbytte 7,41 g, smp. 82-85°C. ;C) [3S(Z)]-[[3-[[(2-amino-4-tiazolyl)(metoksyimino)acetyl]-amino]-2-okso-1-azetidinyl]oksy]eddiksyre-1,1-dimetyletylester ;(S)-[[3-[(benzyloksykarbonyl)amino]-2-okso-1-azetidinyl]-oksy]eddiksyre-1,1-dimetyletyl-ester (1,4 g, 4,0 mmol) ble løst i 25 ml tørr dimetylformamid og hydrogenert med 1 g 10% palladium-på-karbon som katalysator. Etter 20 minutter ble katalysatoren frafiltrert og en blanding av (Z)-2-amino-a-(metoksyimino)-4-tiazoleddiksyre (4,4 mmol), 1-hydroksybenzo-triazolhydrat (0,15 g, 1,0 mmol), dicykloheksylkarbodiimid (0,81 g, 4,4 mmol) og 30 ml tørr dimetylformamid tilsatt. Blandingen ble omrørt over natten ved romtemperatur. Den utfelte dicykloheksylurea ble frafiltrert og løsningsmidlet fjernet under vakuum. Residuet ble løst i etylacetat, vasket med 5% NaHC03og tørket over MgS04. Filtrering og inndamping ;under vakuum førte til tittelforbindelsen som gikk over i fast form ved omrøring med eter/petroleter; smp. 120°C (dekomp.). ;Eksempel 2- 5;Ved å følge fremgangsmåten i eksempel IC.men med forbindelsen angitt i kolonne I i stedet for (Z)-2-amino-a-(metoksyimino)-4-tiazoleddiksyre, ble forbindelsene angitt i kolonne II oppnådd. ; Eksempel 6 ;(3S-trans)-[[3-[(benzyloksykarbonyl)amino]-4-metyl-2-okso-1-azetidinyl] oksy] eddiksyre- 1, 1- dimetylester ;A) 0-(t-butyloksykarbonylmetyl)-a-N-(benzyloksykarbonyl)-L- threonin- hydroksamat ;Ved å følge fremgangsmåten fra eksempel 1A, men med N-a-(benzyloksykarbonyl)-L-threonin i stedet for N-a-(benzyloksykarbonyl ) -L-serin , ble tittelforbindelsen oppnådd i form av en olje som gikk over i fast form ved omrøring med diklormetan/- petroleter over natten; smp. 57-58°C. ;B) (3S-trans)-t[3-[(benzyloksykarbonyl)amino]-4-metyl-2-okso- 1- azetidinyl] oksy] eddiksyre- 1, 1- dimetyletylester ;Ved å følge fremgangsmåten fra eksempel 1B (metode I), men med 0-(t-butyloksykarbonylmetyl)-a-N-(benzyloksykarbonyl)-L-threonin-hydroksamat i stedet for 0-(t-butyloksykarbonyl-metyl) -a-N-(benzyloksykarbonyl)-L-serin-hydroksamat, ble tittelforbindelsen oppnådd. Etter kromatografi og flere ukers lagring i kjøleskap, krystalliserte det oljeaktige produkt; ;smp. ca 30°C.;Eksempel 7 ;(S)-[t 3-[ (benzyloksykarbonyl)amino]-2-okso-1-azetidinyl]-oksy] eddiksyre- difenyImetylester ;A) 0-(difenylmetoksykarbonylmetyl)-a-N-(benzyloksykarbonyl-metyl)- L- serin- hydroksamat ;Ved å følge fremgangsmåten fra eksempel 1A, men med difenylmetylaminooksyacetat i stedet for t-butylaminoksyacetat, ble tittelforbindelsen oppnådd som en rå olje. ;B) (S)-[[3-[(benzyloksykarbonyl)amino]-2-okso-1-azetidinyl]-oksy] eddiksyre- difenylmetylester ;Ved å følge fremgangsmåten fra eksempel 1B (metode II), men med 0-(difenylmetoksykarbonylmetyl)-a-N-(benzyloksy-karbonylmety1)-L-serin-hydroksamat i stedet for ©-(t-butyloksy-karbonylmetyl) -a-N-(benzyloksykarbonyl)-L-serin-hydroksamat, ;ble tittelforbindelsen oppnådd som en olje.;Eksempel 8 ;(3S-trans-2-[[3-[(benzyloksykarbonyl)amino]-4-metyl-2-okso-1-azetidinyl] oksy]- 2- metylpropansyre- difenylmetylester A) 0-[1-metyl-1-(difenylmetoksykarbonyl)etyl]-a-N-(benzyloksykarbonyl)- L- threonin- hydroksamat t ;Ved å følge fremgangsmåten fra eksempel 1A men med N-a-(benzyloksykarbonyl)-L-threonin og difenylmetylaminoksyisobutyrat i stedet for N-a-(benzyloksykarbonyl)-L-serin og t-butylamino-oksyacetat, ble tittelforbindelsen oppnådd. Den ble løst i tørr acetonitril, tørket over molekylarsikt (3Å) ;og inndampet under vakuum til en rå olje.;B) (3S-trans)-2-[[3-[(benzyloksykarbonyl)amino]-4-metyl-2-okso- 1- azetidinyl] oksy]- 2- metylpropansyre- difenylmetylester ;Ved å følge fremgangsmåten i eksempel 1B (metode I) , men med 0-[1-metyl-1-(difenylmetoksykarbonyl)etyl]-a-N-(benzyloksykarbonyl) -L-threonin-hydroksamat i stedet for 0-(t-butyl-oksykarbonylmetyl) -a-N-(benzyloksykarbonyl)-L-serin-hydroksamat, ble tittelforbindelsen oppnådd. Omkrystallisering av det kromatografisk rensede produkt fra eter/petroleter, førte til farveløse krystaller, smp. 115°C (dekomp.). ;Eksempel 9 ;(3S-trans-[ [ 3-[(t-butyloksykarbonyl)amino]-4-mety1-2-okso-1-azetidinyl] oksy] eddiksyre- difenylmetylester ;A) 0-[1-metyl-1-(difenylmetoksykarbonyl)etyl]-a-N-(t-butyloksykarbonyl)- L- threonin- hydroksamat ;Ved å følge fremgangsmåten fra eksempel 1A, men med N-a-(t-butyloksykarbonyl)-L-threonin og difenylmetylaminoksyacetat i stedet for N-a-(benzyloksykarbonyl)-L-serin og t-butylaminoksyacetat, ble tittelforbindelsen oppnådd, ;smp. 87-92°C;B) (3S-trans)-[[3-[(t-butyloksykarbonyl)amino]-4-mety1-2-okso- 1- azetidinyl] oksy] eddiksyre- difenylmetylester ;Ved å følge fremgangsmåten fra eksempel 1B (metode I), men med 0-[1-metyl-1-(difenylmetoksykarbonyl)etyl]-a-N-(t-butyloksykarbonyl)-L-threonin-hydroksamat i stedet for 0-(t-butyloksykarbonylmetyl]-a-N-(benzyloksykarbonyl)-L-serin-hydroksamat, ble tittelforbindelsen oppnådd som en farveløs olje som krystalliserte ved omrøring med petroleter; ;smp. 73-74°C.;Eksempel 10 ;(3S-trans)-[[3-[(benzyloksykarbonyl)amino]-4-metyl-2-okso-1-azetidinyl] oksy] eddiksyre- metylester u ;A) 0-(metoksykarbonylmety1)-a-N-(benzyloksykarbonyl)-L-threonin- hydroksamat ;Ved å følge fremgangsmåten fra eksempel 1A, men med N-a-(benzyloksykarbonyl)-L-threonin og metylaminoksyacetat i stedet for N-a-(benzyloksykarbonyl)-L-serin og t-butylaminoksyacetat, ble tittelforbindelsen oppnådd, smp. ' 99-100°C. ;B) (3S-trans)-[[3-[(benzyloksykarbonyl)amino]-4-metyl-2-okso- 1- azetidinyl] oksy] eddiksyre- metylester ;Ved å følge fremgangsmåten fra eksempel 1B (metode I), men med 0-(metoksykarbonylmetyl)-a-N-(benzyloksykarbonyl)-L-threonin-hydroksamat i stedet for 0-(t-butyloksykarbonyl-metyl ) -a-N-(benzyloksykarbonyl)-L-serin-hydroksamat, ble tittelforbindelsen oppnådd som en farveløs olje. ;Eksempel 11 ;(S) -[[3-t(fenylacetyl)amino]-2-okso-1-azetidinyl]oksy]-eddiksyre- dif eny Ime ty les ter ;A) 0-(difenylmetoksykarbonylmetyl)-a-N-(fenylacetyl)-L-serin- hydroksamat ;Ved å følge fremgangsmåten fra eksempel 1A, men med N-a-(fenylacetyl)-L-serin og difenylmetylaminoksyacetat i stedet for N-a-(benzyloksykarbonyl)-L-serin og t-butylaminoksyacetat, ble tittelforbindelsen oppnådd (kloroform/aceton ble benyttet som eluent ved kromatograferingen),smp. 89-91°C. ;B) (S)-[t 3-[(fenylacetyl)amino]-2-okso-1-azetidinyl]oksy]-eddiksyre- difenylmetylester ;Ved å følge fremgangsmåten fra eksempel 1B (metode I), men med 0-(difenylmetoksykarbonylmetyl)-a-N-(fenylacetyl)-L-serin-hydroksamat i stedet for 0-(t-butyloksykarbonylmetyl)-a-N-(benzyloksykarbonyl)-L-serin-hydroksamat, ble tittelforbindelsen oppnådd som en farveløs olje. ;Eksempel 12 ;(S)-2-[[3-[(fenylacetyl)amino]-2-okso-1-azetidinyl]oksy]-2-metylpropansyre- difenylmetylester ;A) 0-[1-metyl-1-(difenylmetoksykarbonyl)etyl]-a-N-(fenyl-acetyl)- L- serin- hydroksamat ;Ved å følge fremgangsmåten fra eksempel 1A, men med N-a-(fenylacetyl)-L-serin og difenylmetylaminoksyisobutyrat i stedet for N-a-(benzyloksykarbonyl)-L-serin og t-butylaminoksyacetat, ble tittelforbindelsen oppnådd (kloroform/aceton ble benyttet som eluent ved kromatograferingen) i form av en olje som ble løst i tørr acetonitril, tørket over molekylarsikt (3Å) og inndampet under vakuum. ;B) (S)-2-[[3-[(fenylacetyl)amino]-2-okso-1-azetidinyl]-oksy]- 2- metylpropansyre- difenylmetylester ;Ved å følge fremgangsmåten fra eksempel 1B (metode I), men med 0-[1-metyl-1-(difenylmetoksykarbonyl)etyl]-a-N-(fenyl-acetyl) -L-serin-hydroksamat i stedet for 0-(t-butyloksy-karbonylmetyl) -a-N-(benzyloksykarbonyl)-L-serin-hydroksamat, ble tittelforbindelsen oppnådd, smp. 63-73°C dekomp. ;Eksempel 13 ;(3S-trans)-[[3-[(fenylacetyl)amino]-4-metyl-2-okso-1-azetidinyl] oksy] eddiksyre- difenylmetylester ;A) 0-(difenylmetoksykarbonylmetyl)-a-N-(fenylacetyl)-L-threonin- hydroksamat ;Ved å følge fremgangsmåten fra eksempel 1A, men med N-a-(fenylacetyl)-L-threonin og difenylmetylaminoksyacetat i stedet for N-a-(benzyloksykarbonyl)-L-serin og t-butylaminoksyacetat, ble tittelforbindelsen oppnådd, smp. 119-122°C. ;B) (3S-trans)- f[3[(fenylacetyl)amino]-4-metyl-2-okso-1 - azetidinyl] oksy] eddiksyre- difenylmetylester ;Ved å følge fremgangsmåten fra eksempel 1B (metode I), men med 0-(difenylmetoksykarbonylmetyl)-a-N-(fenylacetyl)-L-threonin-hydroksamat i stedet for 0-(t-butyloksykarbonylmetyl)-a-N-(benzyloksykarbonyl)-L-serin-hydroksamat, ble tittelforbindelsen oppnådd som en olje. ;Eksempel 14 ;(3S-trans)-2-[[3-[(fenylacetyl)amino]-4-metyl-2-okso-1-azetidinyl] oksy]- 2- metylpropansyre- difenylmetylester A) 0-[ 1-metyl-1-(difenylmetoksykarbonyl)etyl]-a-N-(fenyl-acetyl)- L- threonin- hydroksamat ;Ved å følge fremgangsmåten fra eksempel 1A, men med N-a-(fenylacetyl)-L-threonin og difenylmetylaminoksyisobutyrat i stedet for N-a -(benzyloksykarbonyl)-L-serin og t-butylaminoksyacetat, ble tittelforbindelsen oppnådd, smp.88°C. ;B) (3S-trans)-2-[[3-[ (fenylacetyl)amino] -4-metyl-2-okso-1-azetidinyl] oksy]- 2- metylpropansyre- difenylmetylester ;Ved å følge fremgangsmåten fra eksempel 1B (metode I),;men med 0-[ 1-metyl-1-difenylmetoksykarbonyl)etyl]-a-N-(fenyl-acetyl)-L-threonin-hydroksamat i stedet for 0-(t-butyloksy-karbonylmetyl) -a-N-(benzyloksykarbonyl)-L-serin-hydroksamat, ble tittelforbindelsen oppnådd, smp. 78°C. dekomp. ;Eksempel 15 ;[3S(Z)]-[[3-[[(2-amino-4-tiazolyl)(metoksyimino)-acetyl]-amino]- 2- okso- 1- azetidinyl] oksy] eddiksyre- kaliumsalt ;N-metyl-N-trimetylsilyltrifluoracetamid (0,20 g, 1,0 mmol) ;(heretter MSTFA) ble tilsatt til en suspensjon av [3S(Z)]-[[3-[[(2-amino-4-tiazolyl)(metoksyimino)acetyl]amino]-2-okso-1-azetidinyl]oksy]eddiksyre-1,1-dimetyletylester (0,20 g, ;0,5 mmol; se eksempel 1) i 5 ml tørr acetonitril ved 0°C. Omrøringen ble fortsatt i 30 minutter ved 0°C og jodtrimetylsilan (0,10 g, 0,5 mmol) ble tilsatt. Etter omrøring i 30 minutter ved romtemperatur, ble blandingen inndampet under vakuum. Residuet ble tatt opp i 5 ml absolutt eter og 0,5 ml metanol ble tilsatt. Presipitatet ble frafiltrert 30 minutter senere, suspendert i 5 ml iskaldt vann, hvorpå pH ble justert til 6,5 med 1N kaliumhydroksyd. Kromatografi (omvendt fase) av suspensjonen på PH-20 resin med vann som eluent, og fryse-tørking av de aktuelle fraksjoner, førte til 120 mg av tittelforbindelsen; smp. >170°C dekomp. ;Eksempel 16 ;[3S(R)]-[[3-[[[[(4-etyl-2,3-diokso-1-piperazinyl)karbonyl]-amino]fenylacetyl]amino]-2-okso-1-azetidinyl]oksy]eddiksyre-natriumsalt ;Fjerning av estergruppen fra [3S(R)]-[13-[[[[(4-ety1-2,3-diokso-1-piperazinyl)karbonyl]amino]fenylacetyl]amino]-2-okso-1-azetidinyl]oksy]eddiksyre-1,1-dimetyletylester (se eksempel 3) ble oppnådd ved hjelp av MSTFA og jodtrimetylsilan som beskrevet i eksempel 15. Etter dekomponering av det rå silylerte produkt med metanol i eter, ble 0,5 ml propylénoksyd og iskaldt vann tilsatt, hvorpå pH ble justert til 6,5 med 5% NaHCO^. Det organiske lag ble fraskilt og den vandige fase frysetørket, hvorved det etter kromatografi på HP-20 med 3:4 vann/aceton som eluent ble oppnådd et utbytte på 230 mg; ;smp. >160°C dekomp.;Eksempel 17 ;[3S-[3a(R),40]]-[[3-[[[[(4-ety1-2,3-diokso-1-piperazinyl)-karbonyl]amino]fenylacetyl]amino]-4-metyl-2-okso-1-azetidinyl]-oksy] eddiksyre- 1, 1- dimetyletylester ;(3S-trans)-[[3-[(benzyloksykarbonyl)amino]-4-metyl-2-okso-1-azetidinyl]oksy]eddiksyre-1,1-dimetyletylester (1,53 g, 4,2 mmol)(se eksempel 6) ble løst i 20 ml tørr dimetylformamid. Etter tilsetning av 1,4 g palladium-på-karbon (10%) katalysator ble en strøm av nitrogen boblet gjennom løsningen i ca 1 time. Etter filtrering ble en reaksjonsblanding (30 minutter, 0°C) bestående av (R)-a-[[(4-etyl-2,3-diokso-1-piperazinyl)karbonyl]-amino]benzeneddiksyre (1,34 g, 4,2 mmol), 1-hydroksy-benzo-triazolhydrat (0,70 g) og dicykloheksylkarbodiimid (0,92 g, ;4,4 mmol) i 30 ml tørr dimetylformamid tilsatt og blandingen omrørt over natten ved romtemperatur. Den utfelte urea ble frafiltrert, løsningsmidlet fjernet under vakuum og residuet kromatografert på kiselgel med etylacetat som eluent. Det oljeaktige produkt krystalliserte ut ved behandling med petroleter. Utbytte: 0,25 g, smp. 103-110°C dekomp. ;Eksempel 18 ;[3S-[3a(Z) ,43]]-[[3-[[(2-amino-4-tiazolyl) (metoksyimino)acetyl] - amino]- 4- metyl- 2- okso- 1- azetidinyl] oksy] eddiksyre- natriumsalt ;MSTFA (0,43 ml, 2,2 mmol) ble tilsatt til en løsning av (3S-trans)-[[3-[(benzyloksykarbonyl)amino]-4-metyl-2-okso-1 - azetidinyl]oksy]eddiksyre-1,1-dimetyletylester (0,73 g, ;2,0 mmol) (se eksempel 6) i 20 ml tørr acetonitril ved 0°C. Jodtrimetylsilan (0,56 ml, 4,4 mmol) ble tilsatt 30 minutter senere ved 0°C, hvorpå omrøringen ble fortsatt i 30 minutter ;ved romtemperatur. Etter inndampning under vakuum, ble residuet løst i 15 ml tørr tetrahydrofuran. (Z)-2-amino-a-(metoksyimino)-4-tiazoleddiksyre-1-hydroksybenzotriazolester (0,64 g, 2,0 mmol) ble tilsatt og blandingen omrørt over natten ved romtemperatur. Løsningsmidlet ble fjernet under vakuum. Etter tilsetning av eter og iskaldt vann, ble pH justert til 6,5 med NaHCO^• Det organiske lag ble fraskilt og den vandige fase frysetørket. Kromatografi på HP-2 0 med 8:2 vann/aceton som eluent, førte ;til tittelforbindelsen (260 mg).;Eksempel 19 ;[3S-[3a(Z),4 3]]-[[3-[[ (2-amino-4-tiazolyl)-[(1-karboksy-1-metyletoksy)imino]acetyl]amino]-4-metyl-2-okso-1-azetidinyl]-oksy] eddiksyre- dinatriumsalt ;Ved å følge fremgangsmåten i eksempel 18, men med (Z)-2-amino-a-[[2-(difenylmetoksy)-1,1-dimetyl-2-oksoetoksy]imino]-4-tiazoleddiksyre-1-hydroksybenzotriazolester i stedet for (Z)-2-amino-a-(metoksyimino)-4-tiazoleddiksyre-1-hydroksybenzo-triazolester, ble det oppnådd [3S-[3a(Z),43]]-[[3-[[(2-amino-4-tiazolyl)]]2-(difenylmetoksy)-1,1-dimetyl-2-oksoetoksy]imino]-acetyl]amino]-4-metyl-2-okso-1-azetidinyl]oksy]eddiksyre-natriumsalt. Produktet ble frysetørket og suspendert i en løsning av trifluoreddiksyre (10 ml) og anisol (1 ml) ved -10°C. Trifluoreddiksyren ble avdestillert 10 minutter senere ved 0°C, hvorpå eter og iskaldt vann ble tilsatt og pH justert til 6,5 med NaHCO^. Etter frysetørking av den vandige fase, ble råproduktet kromatografert på HP-20 med vann som eluent; ;smp. 200°C dekomp.;Eksempel 20- 22;Ved å følge fremgangsmåten i eksempel 1C, men med (3S-trans)-[[3-[(benzyloksykarbonyl)amino]-4-metyl-2-okso-1-azetidinyl]oksy]eddiksyre-metylester (se eksempel 10) i stedet for (S)-[[3-[(benzyloksykarbonyl)amino]-2-okso-1-azetidinyl]-oksy]-eddiksyre-1,1-dimetyletylester og syren angitt i kolonne I i stedet for (Z)-2-amino-a-(metoksyimino)-4-tiazol-eddiksyre, ble forbindelsen angitt i kolonne II oppnådd. 20. (Z)-2-amino-a- [3S-[3a(Z),43]]-[[3-[[(2-(metoksyimino)-4- amino-4-tiazolyl)(metoksy-tiazoleddiksyre imino)]acetyl]amino]-4- metyl-2-okso-1-azetidinyl]-oksy]eddiksyre-metylester; ;smp. 99°C dekomp.;21. (Z)-2-amino-a- [3S-[3a(Z),43]]-t[3-[[(2-[[2-(difenyl- amino-4-tiazolyl)[[2-(difenyl-metoksy) -1,1- metoksy)-1,1-dimetyl-2-okso-dimetyl-2-okso- etoksy]imino]acetyl]amino]-etoksy]imino]-4- 4-metyl-2-okso-1-azetidinyl]-tiazoleddiksyre oksy]eddiksyre-metylester; ;smp. 88-90°C dekomp.;22. (R)-a-[[ (4-etyl-2,3- [3S-[3a(R) ,43]3-t[3-[[[[(4-diokso-1-piperazinyl)- etyl-2,3-diokso-1-piperazinyl)-karbonyl]amino]- karbonyl]amino]fenylacetyl]-benzeneddiksyre amino]-4-metyl-2-okso-1- azetidinyl]oksy]eddiksyre-metylester; smp. 100°C dekomp. ;Eksempel 23;[3S-[3a (Z) , 43]]-[[3-[[(2-amino-4-tiazolyl) [(1-karboksy-1-metyletoksy)imino]acetyl]amino]-4-metyl-2-okso-1-azetidinyl]-oksy] eddiksyre- metylester- natriumsalt ;Ved å benytte trifluoreddiksyre, anisol og natriumbikarbonat (som beskrevet i eksempel 19), ble tittelforbindelsen fremstillet fra [3S-[3a(Z),43]]-[[3-[[(2-amino-4-tiazolyl)-[[2-(difenylmetoksy)-1,1-dimetyl-2-oksoétoksy]imino]acetyl]-amino]-4-metyl-2-okso-1-azetidinyl]oksy]eddiksyre-metylester; smp. ca 19 2°C dekomp. ;Eksempel 24 ;[3S-[3a(R),43]]-[[3-[[[[[(4-metoksyfenyl)metoksy]karbonyl]-amino]fenylacetyl]amino]-4-metyl-2-okso-1-azetidinyl]oksy]-eddiksyre ;(3S-trans)-[[3-[(t-butyloksykarbonyl)amino]-4-metyl-2-okso-1-azetidinyl]oksy]eddiksyre-difenylmetylester (4,4 g, ;10,0 mmol) ble løst i en løsning av 33 ml trifluoreddiksyre og anisol (3,3 ml; 30,0 mmol) ved -10°C. Blandingen ble inndampet under vakuum 10 minutter senere, hvorpå residuet ble omrørt med eter, frafiltrert og tørket over ^ 2^ 5 til rarve10se krystaller av (3S)-[[3-amino-4-metyl-2-okso-1-azetidinyl]-oksy]eddiksyre-trifluoracetatsalt (2,87 g utbytte). Saltet (2,87 g, 10,0 mmol) ble suspendert i tørr acetonitril, tilsatt MSTFA (5,57 ml, 30,0 mmol) og omrøringen fortsatt i 30 minutter. Etter inndampning under vakuum, ble residuet løst i tørr tetrahydrofuran og deretter tilsatt til en blanding av [[[ (4-metoksyfenyl)metoksy]karbonyl]amino]benzeneddiksyre-1-hydroksy-benzotriazolester (4,3 g, 10,0 mmol) i 25 ml tørr tetrahydrofuran ved 0°C, omrørt over natten ved romtemperatur og inndampet under vakuum. Etter tilsetning av eter, ble det rå silylerte produkt dekomponert med 1 ml metanol. Løsnings-midlene ble deretter fjernet under vakuum og residuet omrørt med eter/petroleter, hvorved farveløse krystaller av tittelforbindelsen ble oppnådd. ;Eksempel 25 ;(S)-[[2-okso-3-[(fenylacetyl)amino]-1-azetidinyl]oksy]-eddiksyre- natriumsalt ;(S)-[[3-[(fenylacetyl)amino]-2-okso-1-azetidinyl]-oksy]eddiksyre-difenylmetylester (1,78 g, 4,0 mmol) (se eksempel 11) ble løst i 30 ml absolutt metanol og hydrogenert med 1,2 g 10% palladium-på-karbon som katalysator. Etter 10 minutter ble katalysatoren frafiltrert og filtratet inndampet under vakuum. Residuet ble løst i en blanding ev eter og iskaldt vann og pH justert til 6,5 med NaHCO^. Kromatografi (omvendt fase) av den frysetørkede vandige fase på HP-20 med vann/aceton som eluent, etterfulgt av frysetørking av de aktuelle fraksjoner, førte til 255 mg av tittelforbindelsen, smp. 56-70°C dekomp. ;Eksempel 26 ;(S)-2-[[2-okso-3-[(fenylacetyl)amino]-1-azetidinyl]oksy]-2- metylpropansyre- natriumsalt ;Ved å følge fremgangsmåten i eksempel 25, men med 4,0 mmol (S)-2-[[3-[(fenylacetyl)amino]-2-okso-1-azetidinyl]oksy]-2-' metylpropansyre-difenylmetylester (se eksempel 12) i stedet for 4,0 mmol (S)-[[3-[(fenylacetyl)amino]-2-okso-1-azetidinyl]-oksy]eddiksyre-difenylmetylester, ble 630 mg av tittelforbindelsen oppnådd, smp. 88°C. ;Eksempel 27 ;(3S-trans)-[[4-metyl-2-okso-3-[(fenylacetyl)amino]-1-azetidinyl] oksy] eddiksyre- natriumsalt ;Ved å følge fremgangsmåten i eksempel 25, men med (3S-trans)-[[3-[(fenylacetyl)amino]-4-metyl-2-okso-1-azetidinyl]-oksy]eddiksyre-difenylmetylester (se eksempel 13) i stedet for (S)-[[3-[(fenylacetyl)amino]-2-okso-1-azetidinyl]oksy]eddiksyre-dif eny lmetylester , ble tittelforbindelsen oppnådd, ;smp. 77-130°C dekomp.;Eksempel 28 ;(3S-trans)-2-[[4-metyl-2-okso-3-[(fenylacetyl)amino]-1-azetidinyl] oksy]- 2- metylpropansyre- natriumsalt ;Ved å følge fremgangsmåten i eksempel 15, men med (3S-trans)-2-[[3-[(fenylacetyl)amino]-4-metyl-2-okso-1-azetidinyl]oksy]-2-metylpropansyre-difenyImetylester (se eksempel 14 ), i stedet for (S)-[[3-[(fenylacetyl)amino]-2-okso-1-azetidinyl]oksy]eddiksyre-difenylmetylester, ble tittelforbindelsen oppnådd, smp. 135-14 5°C dekomp. ;Eksempel 29 ;(3S-trans)-2-[[3-[(benzyloksykarbonyl)amino]-4-metyl-2-okso-1- azetidinyl] oksy]- 2- metylpropansyre ;(3S-trans)-2-[[3-[(benzyloksykarbonyl)amino]-4-metyl-2-okso-1-azetidinyl]oksy]-2-metylpropansyre-difenylmetylester (1,51 g, 3,0 mmol) (se eksempel 8), ble omrørt med en løsning av 1 ml anisol i 10 ml trif luoreddiksyre ved -10°C i 10 minutter. Blandingen ble inndampet under vakuum og residuet løst i eter. Etter tilsetning av petroleter ble det resulterende presipitat oppsamlet; utbytte 0,85 g, smp. 125-126°C dekomp. ;Eksempel 30 ;[3S-[3a(Z),43]]-2-[[3-[[(2-amino-4-tiazolyl)(metoksyimino)-acetyl]amino]-4-metyl-2-okso-1-azetidinyl]oksy]-2-metylpropansyre- natriumsalt ;Ved å følge fremgangsmåten i eksempel 18, men med (3S-trans)-2-[[3-[(benzyloksykarbonyl)amino]-4-metyl-2-okso-1-azetidinyl]oksy]-2-metylpropansyre (se eksempel 29) i stedet for (3S-trans)-[[3-[(benzyloksykarbonyl)amino]-4-metyl-2-okso-1-azetidinyl]oksy]eddiksyre-1,1-dimetyletylester, ble tittelforbindelsen oppnådd, smp. >190°C dekomp. ;Eksempel 31 ;(3S-trans)-2-[[3-[(benzyloksykarbonyl)amino]-4-metyl-2-okso- 1- azetidinyl] oksy]- 2- metylpropansyre- metylester , ;Til en omrørt suspensjon av (3S-trans)-2-[[3-[(benzyloksykarbonyl ) amino]-4-metyl-2-okso-1-azetidinyl]oksy]-2-metylpropansyre (1,68 g, 5,0 mmol) (se eksempel 29) i 10 ml tørr diklormetan, ble tilsatt 4-dimetylaminopyridin (30 mg), tørr metanol (0,81 ml, 210 mmol) og dicykloheksylkarbodiimid (1,13 g, 5,5 mmol) ved 0°C. Reaksjonsblandingen ble omrørt i 3 timer ved romtemperatur. Presipitatet (dicykloheksylurea) ble fjernet ved filtrering og filtratet inndampet under vakuum. Residuet ble tatt opp i eter, filtrert, vasket med vandig bufferløsning pH 4 (citrat/HCl), NaHCG^-løsning, tørket over MgSO^og filtrert. Inndampning under vakuum ga tittelforbindelsen. ;Eksempel 32 ;[3S-[3a(Z) ,43]]-2-[[3-[[(2-amino-4-tiazolyl) [[ (1-karboksy-1-metyl)etoksy]imino]acetyl]amino]-4-metyl-2-okso-1-azetidinyl]-oksy]- 2- metylpropansyre- metylester- natriumsalt ;Ved å følge fremgangsmåten i eksemplene 1C og 23, men med (3S-trans)-2-[[3-[(benzyloksykarbonyl)amino]-4-metyl-2-okso-1-azetidinyl]oksy]-2-metylpropansyre-metylester (se eksempel. 31), ble tittelforbindelsen oppnådd, smp. >150°C dekomp. ;Eksempel 33 ;(3S-trans)-[[3-[(t-butyloksykarbonyl)amino]-4-metyl-2-okso-1- azetidinyl] oksy] eddiksyre- difenylmetylester ;A) (3S-trans)-3-(t-butyloksykarbonylamino)-1-hydroksy-4-metyl- 2- azetidinon ;(3S-trans)-3-(t-butyloksykarbonylamino)-1-benzyloksy-4-metyl-2-azetidinon (10,2 g, 33,3 mmol) ble løst i tørr metanol og hydrogenert med 1,66 g palladium-på-karbon (10%) som katalysator. Etter 4 5 minutter ble katalysatoren frafiltrert og filtratet inndampet til tørrhet ved redusert trykk. ;Omrøring av residuet (6,94 g) med eter/petroleter ga tittelforbindelsen; utbytte 6,6 0 g, smp. >144°C dekomp. ;B) (3S-trans)-[[3-[(t-butyloksykarbonyl)amino]-4-metyl-2-okso- 1- azetidinyl] oksy] eddiksyre- difenylmetylester ;Trietylamin (0,61 g, 6,0 mmol) ble dryppet inn i en løsning av (3S-trans)-3-(t-butyloksykarbonylamino)-1-hydroksy-4-metyl-2-azetidinon (1,08 g, 5,0 mmol) og difenylmetylkloracetat (1,43 g, 5,5 mmol) i 10 ml tørr dimetylformamid. Blandingen ble omrørt over natten ved romtemperatur. Presipitatet ble fjernet ved filtrering og løsningsmidlet avdrevet under vakuum. Residuet ble tatt opp i etylacetat, filtrert, vasket med 5% NaHCO^-løsning og vann, tørket over MgSO^og inndampet under vakuum til en farveløs olje; ;utbytte 2,0 g. Ved oppbevaring i kjøleskap ble tittelforbindelsen utkrystallisert, smp. 73-74°C. ;Eksempel 34 ;(3S-trans)-[[3-[(t-butyloksykarbonyl)amino]-4-metyl-2-okso-1-azetidinyl] oksy] eddiksyre- 1, 1- dimetyletylester ;Ved å følge fremgangsmåten i eksempel 3 3B, men med t-butylkloracetat i stedet for difenylmetylkloracetat, ble tittelforbindelsen oppnådd som en olje som utkrystalliserte ved oppbevaring i kjøleskap. ;Eksempel 35 ;(3S-trans)-[(3-amino-4-mety1-2-okso-1-azetidinyl)oksy]eddiksyre- 1, 1- dimetyletylester ;(3S-trans)-[[3-[(t-butyloksykarbonyl)amino]-4-metyl-2-okso-1-azetidinyl]oksy]eddiksyre-1,1-dimetyletylester (1,44 g, 4,4 mmol) (se eksempel 34) ble løst i en blanding av 8,8'ml trifluoreddiksyre og 0,88 ml anisol ved -10°C. Løsningen ble inndampet under vakuum 10 minutter senere ved 0°C og residuet omrørt med eter, frafiltrert og tørket over P2^5 farveløse krystaller av trifluoracetatsaltet av tittelforbindelsen; utbytte 0,61 g, smp. 111-112°C dekomp. ;Saltet (1,38 g, 4,0 mmol) ble suspendert i tørr aceto-avdestillert under vakuum og residuet tatt opp i etylacetat, vasket suksessivt med vann, NaHCO^-løsning og vann, og deretter tørket (N.a^SO^). Etter fjerning av løsningsmidlet under vakuum, ble den resulterende olje omrørt med petroleter og den uløse-lige olje fraskilt (0,86 g) og renset ved kromatografi på ;SiC>2med en blanding av etylacetat/eter (1:3) som eluent, hvilket ga en farveløs olje; utbytte 0,43 g. ;Eksempel 38 ;(3S-cis)-[(3-amino-4-metyl-2-okso-1-azetidinyl)oksy]eddiksyre- trifluoracetatsalt ;A) 0-(difenylmetoksykarbonylmetyl)-N-t-butyloksykarbonyl-allo- L- threonin ;Ved å følge fremgangsmåten i eksempel 1A, men med N-t-butyloksykarbonyl-allo-L-threonin og difenylmetylaminooksyacetat i stedet for N-a-(benzyloksykarbonyl)-L-serin og t-butylaminooksyacetat, ble tittelforbindelsen oppnådd, ;smp. 140-143°C ;B) (3S-cis)-[[3-[(t-butoksykarbonyl)amino]-4-metyl-2-okso-azetidinyl ] oksy ] eddiksyre- dif eny lmety le ster ;Ved å følgé fremgangsmåten fra eksempel 1B (metode I), men med 0-(difenylmetoksykarbonylmetyl)-N-t-butyloksykarbonyl-allo-L-threonin i stedet for 0-(t-butyloksykarbonylmetyl)-a-N-(benzyloksykarbonyl)-L-serih-hydroksamat, ble tittelforbindelsen oppnådd. Etter kromatografi på kiselgel med etylacetat/eter som eluent gikk det oljeaktige produkt over i fast form ved omrøring med petroleter; smp. 105-108°C. ;C) (3S-cis)-[(3-amino-4-metyl-2-okso-1-azetidinyl)oksy]-eddiksyre- trifluoracetatsalt ;(3S-cis)-[[3-[(t-butoksykarbonyl)amino]-4-metyl-2-okso-1-azetidinyl]oksy]eddiksyre-difenylmetylester (1,5 g, 3,5 mmol) ble løst i en blanding av 15 ml trifluoreddiksyre og 1,5 ml anisol ved -10°C. Etter henstand ved 0°C i 10 minutter, ble 30 ml eter tilsatt. Presipitatet ble frafiltrert, vasket med eter og tørket under vakuum over P2°5til et hycjros>copisk faststoff; utbytte 0,53 g. ;Eksempel 39 ;(3S-trans)-[[3-[(t-butyloksykarbonyl)amino]-4-metyl-2-okso-1- azetidinyl] oksy] eddiksyre- fenylmetylester ;A) N 2-( t- butyloksykarbonyl)- N-( fenylmetoksy)- L- threoninamid N-(t-butyloksykarbonyl)-L-threonin (82,2 g) ble løst i en liter etylacetat og tilsatt 40,5 g dimetyl(fenylmety1)amin. Etter omrøring i 10 minutter, ble blandingen avkjølt til -10°C og dråpevis tilsatt 31,05 g metylklor-formiat. Blandingen ble omrørt i 30 minutter ved -10°C, hvorpå en løsning av 4 0,65 g (fenylmetoksy)amin i 300 ml etylacetat ble tilsatt ved -10°C. Temperaturen fikk deretter stige til 5°C i løpet av en 90 minutters periode. Reaksjonsblandingen ble deretter inndampet under vakuum og løst opp igjen i en liter etylacetat. Det uløselige materiale ble frafiltert og, under kjøling, vasket med vann, fortynnet saltsyre (pH av vandig fase ikke under 2,5), natriumbikarbonat- og saltoppløsning. Etter tørking (MgS04) og fjerning av løsningsmidlet under vakuum, ble det oppnådd en olje som krystalliserte ved behandling med petroleter og ga 79,4 g av tittelforbindelsen, smp. 87°C. ;B) N 2-(t-butyloksykarbonyl)-0-(metylsulfonyl)-N-(fenyl-metoksy)- L- threoninamid ;N 2-(t-butyloksykarbonyl)-N-(fenylmetoksy)-L-threoninamid (244 g) ble løst i 1,2 liter pyridin og løsningen avkjølt til 0°C. Under omrøring ved 0-5°C ble det dråpevis tilsatt 120 g metansulfonylklorid. Etter 2,5 timer ble reaksjonsblandingen heilt over i en blanding av 1500 ml 2N saltsyre og is, og pH av blandingen justert til 4 ved tilsetning av konsentrert HC1. Tittelforbindelsen krystalliserte ut og ble etter 1 time, frafiltrert og vasket med vann og petroleter. Etter tørking ved romtemperatur ble det oppnådd 356,4 g som inneholdt en god del vann; smp. 128-130°C dekomp. ;C) (3S-trans)-3-[(t-butyloksykarbonyl)amino]-4-metyl-2-okso- 1-( fenylmetoksy) azetidin ;Kaliumkarbonat (200 g) ble løst i 300 ml vann, tilsatt 1,5 liter 1,2-dikloretan og blandingen tilbakeløpsbehandlet. En suspensjon av 178 g N 2-(t-butyloksykarbonyl)-0-(metyl- ;41. (3S-trans)-[[3-[(t-butyloksykarbonyl)amino]-4-metyl-2-okso-1-azetidinyl]oksy]eddiksyre-2-hydroksyetylester 4 2. (3S-trans)-[[3-[(t-butyloksykarbonyl)amino]-4-metyl-2-okso-1-azetidinyl]oksy]eddiksyre-2-metoksyetylester 43. (3S-trans)-[[3-[(t-butyloksykarbonyl)amino]-4-metyl-2-okso-1-azetidinyl]oksy]eddiksyre-2-metylpropylester 44. (3S-trans)-[[3-[(t-butyloksykarbonyl)amino]-4-metyl-2-okso-1-azetidinyl]oksy]eddiksyre-1-etylpropylester 45. (3S-trans)-[[3-[(t-butyloksykarbonyl)amino]-4-mety1-2-okso-1-azetidinyl]oksy]eddiksyre-fenylester 46. (3S-trans)-[[3-[(t-butyloksykarbonyl)amino]-4-metyl-2-okso-1-azetidinyl]oksy]eddiksyre-2-metylfenylester 47. (3S-trans)-[[3-[(t-butyloksykarbonyl)amino]-4-metyl-2-okso-1 -azetidi-nyl ] oksy ] eddiksyre-5-indanylester 48. (3S-trans)-[[3-[(t-butyloksykarbonyl)amino]-4-mety1-2-okso-1-azetidinyl]oksy]eddiksyre-2-indanylester 49. (3S-trans)-[[3-[(t-butyloksykarbonyl)amino]-4-metyl-2-okso-1-azetidinyl]oksy]eddiksyre-(5-metyl-2-okso-1,3-dioksol-4-yl)metylester 50. (3S-trans)-[[3-[(t-butyloksykarbonyl)amino]-4-metyl-2-okso-1-azetidinyl]oksy]eddiksyre-(2,2-dimetyl-1-oksopropoksy)-metylester ;Eksempel 51 ;(3S-trans)-[(3-amino-4-metyl-2-okso-1-azetidinyl)oksy]eddiksyre-f eny Ime ty le ster- tr if luoracetatsalt ;(3S-trans)-[[3-[(t-butyloksykarbonyl)amino]-4-metyl-2-okso-1-azetidinyl]oksy]eddiksyre-fenylmetylester (3,6 g) ble ;løst i 5 ml diklormetan og løsningen avkjølt til -10°C. Trifluoreddiksyre (25 ml) ble dråpevis tilsatt og blandingen om-rørt i 20 minutter ved -10°C. Etter inndamping ble residuet behandlet med eter, hvorved 2,5 g av tittelforbindelsen ble oppnådd. ;Eksempel 52- 62;Ved å følge fremgangsmåten i eksempel 51, men med den passende ester i stedet for (3S-trans)-[[3-[(t-butyloksykarbonyl) amino]-4-metyl-2-okso-1-azetidinyl]oksy]eddiksyre-fenylmetylester, ble de nedenfor angitte forbindelser oppnådd. 52. (3S-trans)-[(3-amino-4-metyl-2-okso-1-azetidinyl)oksy]-eddiksyre-etylester-trifluoracetatsalt 53. (3S-trans)-[(3-amino-4-metyl-2-okso-1-azetidinyl)oksy]-eddiksyre-2-hydroksyetylester-trifluoracetatsalt 54. (3S-trans)-[(3-amino-4-metyl-2-okso-1-azetidinyl)oksy]-eddiksyre-2-metoksyetylester-trifluoracetatsalt 55. (3S-trans)-[(3-amino-4-metyl-2-okso-1-azetidinyl)oksy]-eddiksyre-2-metylpropylester-trifluoracetatsalt 56. (3S-trans)-[(3-amino-4-metyl-2-okso-1-azetidinyl)oksy]-eddiksyre-1-etylpropylester-trifluoracetatsalt 57. (3S-trans)-[(3-amino-4-metyl-2-okso-1-azetidinyl)oksy]-eddiksyre-fenylester-trifluoracetatsalt 58. (3S-trans)-[(3-amino-4-metyl-2-okso-1-azetidinyl)oksy]-eddiksyre-2-metylfenylester-trifluoracetatsalt 59. (3S-trans)-[(3-amino-4-metyl-2-okso-1-azetidinyl)oksy]-eddiksyre-5-indanylester-trifluoracetatsalt 60. (3S-trans)-[(3-amino-4-metyl-2-okso-1-azetidinyl)oksy]-eddiksyre-2-indanylester-trifluoracetatsalt 61. (3S-trans)-[(3-amino-4-metyl-2-okso-1-azetidinyl)oksy]-eddiksyre-(5-metyl-2-okso-1,3-dioksol-4-yl)metylester-trifluoracetatsalt ~ 62. (3S-trans)-[(3-amino-4-metyl-2-okso-1-azetidinyl)oksy]-eddiksyre-(2,2-dimetyl-1-okso-etoksy)metylester-trifluoracetatsalt Eksempel 63 [3S-[3a(Z) ,4 3] ]-[[3-[ [ (2-amino-4-tiazolyl) (metoksyimino) acetyl]-amino]-4-metyl-2-okso-1-azetidinyl]oksy]eddiksyre-fenylmety1-ester (Z)-2-amino-a-(metoksyimino)-4-tiazoleddiksyre (1,32 g) ble løst i 22 ml absolutt dimetylformamid og tilsatt 1,1 mol trietylamin, hvorpå blandingen ble avkjølt til -25°C. Difenyl-fosfokloridat (1,36 ml) ble tilsatt og temperaturen holdt ved -25°C i 50 minutter. Blandingen ble deretter tilsatt til en løsning fremstillet av 2,5 g (3S-trans)-[(3-amino-4-metyl-2-okso-1-azetidinyl)oksy]eddiksyre-fenylmetylester-trifluoracetatsalt og 4,6 ml trietylamin i 22 ml dimetylformamid som også var avkjølt til -25°C. Reaksjonsblandingen ble omrørt ved -25°C i 2,5 timer og under omrøring tilsatt 70 ml 0,5 molar monobasisk kaliumfosfat, fortynnet med 70 ml vann og ekstrahert med etylacetat. Ved tilsetning av 2N saltsyre ble pH justert til 6. Den vandige fase ble ekstrahert igjen med etylacetat og de samlede organiske faser vasket med vann, tørket med MgSO^, filtrert og inndampet til 2,3 g tittelforbindelse i form av et skum som ble behandlet med petroleter og filtrert. ;Eksempel 64- 66;Ved å følge fremgangsmåten i eksempel 63, men med den passende ester i stedet for (3S-trans)-[(3-amino-4-metyl-2-okso-1-azetidinyl)oksy]eddiksyre-fenylmetylester-trifluoracetatsalt, ble de nedenfor angitte forbindelser oppnådd. 64. [3S-[3a(Z),43]]-[[3-[[(2-amino-4-tiazolyl)(metoksyimino)-acetyl]amino]-4-metyl-2-okso-1-azetidinyl]oksy]eddiksyre-(5-metyl-2-okso-1,3-dioksol-4-yl)metylester 65. [3S-[3a(Z),43]]-[[3-[[(2-amino-4-tiazolyl)(metoksyimino)-acetyl]amino]-4-metyl-2-okso-1-azetidinyl]oksy]eddiksyre-(2,2-dimetyl-1-okso-propoksy)metylester 66. [3S-[3a(Z),43]]-[[3-[[(2-amino-4-tiazolyl)(metoksyimino)-acetyl]amino]-4-metyl-2-okso-1-azetidinyl]oksy]eddiksyre-[ (1 - metyletyl)karbamoyl]metylester ;Eksempel 6 7 ;[3S-[3a(Z) ,43]]-[[3-[[(2-amino-4-tiazolyl) (metoksyimino)-acetyl]amino]-4-metyl-2-okso-1-azetidinyl]oksy]eddiksyre-fenylester ;(3S-trans)-[(3-amino-4-metyl-2-okso-1-azetidinyl)oksy]-eddiksyre-fenylester-trifluoracetatsalt (2,1 g) ble suspendert i 50 ml acetonitril og 2,1 g N-metyl(trimetylsilyl)trifluor-metylacetamid ble tilsatt for å oppnå en oppløsning. Etter avkjøling til 0°C, ble (Z)-2-amino-a-(metoksyimino)-4-tiazoleddiksyre-N-hydroksybenzotriazolester tilsatt. Blandingen ble omrørt i 3 timer ved romtemperatur, inndampet under vakuum, løst opp igjen i etylacetat, vasket (kjøling) med saltoppløsning som under vaskingen ble justert til pH 7. Den organiske fase ble tørket (MgSO^) inndampet og residuet behandlet med eter, hvorved 2,6 g av tittelforbindelsen ble oppnådd. ;Eksempel 68- 73;Ved å følge fremgangsmåten i eksempel 67, men med den passende ester i stedet for (3S-trans)-[(3-amino-4-metyl-2-okso-1-azetidinyl)oksy]eddiksyre-fenylester-trifluoracetatsalt, ble de nedenfor angitte forbindelser oppnådd. 68. [3S-[3a(Z),43]]-[[3-[[(2-amino-4-tiazolyl)(metoksyimino)-acetyl]amino]-2-okso-1-azetidinyl]oksy]eddiksyre-etylester 69. [3S-[3a(Z),43]]-[[3-[[(2-amino-4-tiazolyl)(metoksyimino)-acetyl]amino]-2-okso-1-azetidinyl]oksy]eddiksyre-2-hydroksy-etylester 70. [3S-[3a(Z),43]]-[[3-[[(2-amino-4-tiazolyl)(metoksyimino)-acetyl]amino]-2-okso-1-azetidinyl]oksy]eddiksyre-2-metoksy-etylester 71 . [3S-[3a(Z) ,43]]-[[3-[[(2-amino-4-tiazolyl) (metoksyimino)-acetyl]amino]-2-okso-1-azetidinyl]oksy]eddiksyre-2-metyl-propylester 72. [3S-[3a(Z),43]]-[[3-[[(2-amino-4-tiazolyl)(metoksyimino)-acetyl]amino]-2-okso-1-azetidinyl]oksy]eddiksyre-1-etylpropylester 73. [3S-[3a(Z),43]]-[[3-[[(2-amino-4-tiazolyl)(metoksyimino)-acetyl]amino]-2-okso-1-azetidinyl]oksy]eddiksyre-2-indanyl-ester ;Eksempel 74 ;(3S-trans)-[[3-[(t-butyloksykarbonyl)amino]-4-metyl-2-okso- 1- azetidinyl] oksy] eddiksyre- kaliumsalt ;(3S-trans)-[[3-[(t-butyloksykarbonyl)amino]-4-metyl-2-okso-1-azetidinyl]oksy]eddiksyre-fenylmetylester (3,6 g) ble løst i 100 ml metanol. Etter behandling med aktiv-kull ble det tilsatt 1,8 g 5% palladium-på-karbon og hydrogen ført inn gjennom den omrørte blanding ved romtemperatur. Etter 1 time ble blandingen filtrert, hvorpå filtratet ble fortynnet med ;vann, nøytralisert med kaliumkarbonat og lyofilisert, hvorved tittelforbindelsen ble oppnådd. ;Eksempel 75 ;(3S-trans)-[[3-[(t-butyloksykarbonyl)amino]-4-metyl-2-okso-1-azetidinyl]oksy]eddiksyre-(2,2-dimetyl-1-oksopropoksy)metylester _ ;(3S-trans)-[[3-[(t-butyloksykarbonyl)amino]-4-metyl-2-okso-1-azetidinyl]oksy]eddiksyre-kaliumsalt (0,01 mol) ble løst i 40 ml dimetylformamid. Løsningen ble avkjølt til 0°C og tilsatt 0,7 ml trietylamin og deretter 3,1 g 2,2-dimetyl-propionsyre-jodmetylester. Etter omrøring over natten ved 0°C, ble løsningsmidlet fjernet under vakuum og det oljeaktige residuum løst i 100 ml etylacetat, vasket 3 ganger med isvann, tørket (MgSO^) og inndampet til 2,4 g av tittelforbindelsen. ;Eksempel 76- 78;Ved å følge fremgangsmåten i eksempel 75, men med den passende forbindelse i stedet for 2,2-dimetylpropionsyre-jodmetylester, ble de nedenfor angitte forbindelser oppnådd. 76. (3S-trans)-[[3-[(t-butyloksykarbonyl)amino]-4-mety1-2-okso-1-azetidinyl]oksy]eddiksyre-(5-metyl-2-okso-1,3-dioksol-4-yl)metylester 77. (3S-trans)-[[3-[(t-butyloksykarbonyl)amino]-4-metyl-2-okso-1-azetidinyl]oksy]eddiksyre-[(1-metyletyl)karbamoyl]-metylester 78. (3S-trans)-[[3-[(t-butyloksykarbonyl)amino]-4-metyl-2-okso-1-azetidinyl]oksy]eddiksyre-[(2,2-dimetyletyl)karbamoyl]-metylester ;Eksempel 79 ;(S)-[[3-[(benzyloksykarbonyl)amino]-2-okso-1-azetidinyl]oksy]-eddiksyre ;(S)-[[3-[(benzyloksykarbonyl)amino]-2-okso-1-azetidinyl]-oksy]eddiksyre-difenylmetylester (15,4 g; se eksempel 7), ble blandet med 4 ml anisol. Ved 0°C ble 4 0 ml trifluoreddiksyre langsomt tilsatt og blandingen holdt ved denne temperatur i 10 minutter. Reaksjonsblandingen ble inndampet under vakuum ved romtemperatur, løst i etylacetat og inndampet igjen. Det oljeaktige residuum ble løst i 100 ml etylacetat, tilsatt iskaldt vann og pH av blandingen justert til 6,5. Etylacetatfasen ble deretter ekstrahert nok en gang med fortynnet natriumbikarbonat-løsning. ;De kombinerte vandige faser ble avkjølt (is), ekstrahert med 100 ml etylacetat og tilsatt 2N saltsyre til pH 2. Den vandige fase ble ekstrahert 2 ganger til med etylacetat og de kombinerte etylacetatekstrakter tørket (MgSO^) og inndampet, hvorved 6 g av tittelforbindelsen ble oppnådd som et sirupøst produkt. ;Tittelforbindelsen ble løst i en blanding av metanol og vann og løsningen justert til pH 6>5 med fortynnet natrium-hydroksyd og frysetørket, hvorved det korresponderende natriumsalt ble oppnådd som et amorft faststoff. ;Eksempel 30 ;(S)-[[3-[(benzyloksykarbonyl)amino]-2-okso-1-azetidinyl]-oksy] eddiksyre-( 2, 2- dimetyl- 1- oksopropoksy) metylester ;(S)-[[3-[(benzyloksykarbonyl)amino]-2-okso-1-azetidinyl]-oksy]eddiksyre (3 g; se eksempel 79) ble løst i 200 ml dimetylformamid og løsningen avkjølt til 0°C. 1,8-diazabicyklo-[5.4.0]-undek-7-en (0,01 mol) og deretter 2,7 g 2,2-dimetyl-propionsyre-jodmetylester ble tilsatt. Etter 10 minutter ble blandingen fortynnet med 75 ml etylacetat, avkjølt (isvann) og vasket med iskaldt vann, iskald fortynnet natriumbikarbonat-løsning og igjen med iskaldt vann. Etter tørking (MgSO^) ble filtratet inndampet, hvorpå det ved henstand utkrystallisertes 4 g av tittelforbindelsen; smp. 73-75°C. ;Eksempel 81 ;(S)-[[3-[(benzyloksykarbonyl)amino]-2-okso-1-azetidinyl]-oksy] eddiksyre-[( 2, 2- dimetyletoksy) karbonyl] metylester, ;Ved å følge fremgangsmåten i eksempel 80, men med klor-eddiksyre-1,1-dimetyletylester i stedet for 2,2-dimetyl-propionsyre-jodmetylester, og ved å la reaksjonen strekke seg over 6 timer, ble tittelforbindelsen oppnådd; smp. 90-92°C. ;Eksempel 82 ;[3S-[3a(Z),43]]-[[3-[[2-[[(trifenylmetyl)amino]-4-tiazolyl]-[metoksyimino]acety1]amino]-2-okso-1-azetidinyl]oksy]eddiksyre- 1 - etylpropylester ;A) N-[[2-[(trifenylmetyl)amino]-4-tiazolyl][metoksyimino]-acetyl]- L- threonin ;< L-threonin (11 g) ble suspendert i 140 ml acetonitril. Etter tilsetning av 46 ml bistrimetylsilylacetamid ble blandingen tilbakeløpsbehandlet i 1 time. ;(Z)-2-[(trifenylmetyl)amino]-a-(metoksyimino)-4-tiazol-eddiksyre (48,4 g) ble løst i 250 ml dimetylformamid og tilsatt 15,9 g N-hydroksybenzotriazol og 24,1 g dicykloheksylkarbodiimid. Blandingen ble omrørt i 2 timer ved romtemperatur. Krystallene (dicykloheksylurea) ble frafiltrert og filtratet inndampet under vakuum, hvorpå residuet ble løst i 300 ml acetonitril og kombinert^med løsningen av silylert L-threonin. Blandingen ble omrørt over natten ved romtemperatur, filtrert, inndampet under vakuum, behandlet med vann og den vandige fase justert til pH 7,5 og ekstrahert med etylacetat. Den vandige fase ble deretter tilsatt 2N saltsyre til pH 2,5. Tittelforbindelsen utfeltes og ble frafiltrert (46,9 g). ;B) N 2-[[ 2-[ (trif enylmetyl) amino]-4-tiazolyl][metoksyimino] - acetyl]- N-[[( difenylmetoksy) karbonyl] metoksy]- L- threoninamid ;N-[[2-[(trifenylmetyl)amino]-4-tiazolyl] [ metoksyimino]-acetyl]-L-threonin ble omsatt med [[(difenylmetoksy)karbonyl]-metoksylamin ifølge fremgangsmåten beskrevet i eksempel 39A, hvorved tittelforbindelsen ble oppnådd som et amorft faststoff. C) N -[[2-[(trifenylmetyl)amino]-4-tiazolyl][metoksyimino]-acetyl]-O-(metylsulfonyl)-N-[[(difenylmetoksy)karbonyl]-metoksy]- L- threoninamid ;N 2-[[2-[(trifenylmetyl)amino]-4-tiazolyl][metoksyimino]-acetyl]-N-[[(difenylmetoksy)karbonyl]metoksy]-L-threoninamid ble mesylert ifølge fremgangsmåten beskrevet i eksempel 39B, hvorved tittelforbindelsen ble oppnådd som et amorft faststoff. ;D) [3S-[3a(Z),43]]-[[3-[[2-[[(trifenylmetyl)amino]-4-tiazolyl][metoksyimino]acetyl]amino]-2-okso-1-azetidinyl]-oksy ] eddiksyre- dif enylm etylester ;N 2-[[2-[(trifenylmetyl)amino]-4-tiazolyl][metoksyimino] acetyl ] -0- (metylsulfonyl)-N-[[(difenylmetoksy)karbonyl]-metoksy]-L-threoninamid ble behandlet med kaliumkarbonat ifølge fremgangsmåten beskrevet i eksempel 39C, hvorved tittelforbindelsen ble oppnådd. ;Eksempel 83 ;[3S-[3a(Z),4 3]]-[[3-[[2-[[(trifenylmetyl)amino]-4-tiazolyl]-[metoksyimino]acetyl]amino]-2-okso-1-azetidinyl]oksy]eddiksyre- 1 - etylpropylester ;Ved å følge fremgangsmåten i eksempel 82, men med [[(1-etylpropoksy)karbonyl]metoksy]amin i stedet for [[(difenyl-metoksy) karbonyl ]metoksy]amin , ble tittelforbindelsen oppnådd. ;Eksempel 84;(alternativ fremstilling av forbindelsen i eksempel 72);[3S-[3ot(Z) ,43] ]-[ [3-[ [ (2-amino-4-tiazolyl) (metoksyimino)-acetyl]amino]-2-okso-1-azetidinyl]oksy]eddiksyre-1-etylpropylester ;[3S-[3a(Z),43]]-[[3-[[2-[[(trifenylmetyl)amino]-4-tiazolyl][metoksyimino]acetyl]amino]-2-okso-1-azetidinyl]-oksy]eddiksyre-1-etylpropylester (1,2 g) ble løst i 12 ml 97% maursyre ved romtemperatur. Etter omrøring i 4 timer, ble blandingen filtrert og filtratet blandet med 35 ml diklormetan. Det ble deretter tilsatt vann, hvoretter den organiske fase ble ;vasket med vann og fortynnet natriumbikarbonat, tørket (MgSO^) og inndampet til 0,4 3 g av tittelforbindelsen. ;Eksempel 85 ;[3S-[3a(Z),40]]-[[3-[[(2-amino-4-tiazolyl)(metoksyimino)-acetyl]amino]-2-okso-1-azetidinyl]oksy]eddiksyre-difeny1-metylester ;Ved å følge fremgangsmåten i eksempel 84, men med [3S-[3a(Z),43]]-[[3-[[2-[[(trifenylmetyl)amino]-4-tiazolyl][metoksyimino ]acetyl]amino]-2-okso-1-azetidinyl]oksy]eddiksyre-dif enylmetylester i stedet for [3S-[3a(Z),40]]-[[3-[[2-[(tri-fenylmetyl)amino]-4-tiazolyl][metoksyimino]acetyl]amino]-2-okso-1-azetidinyl]oksy]eddiksyre-1-etylpropylester, ble tittelforbindelsen oppnådd. ;Eksempel 86;[3S-[3a(Z), 43]]-[[3-[[(2-amino-4-tiazolyl)(metoksyimino)-acetyl]amino]-4-metyl-2-okso-1-azetidinyl]oksy]eddiksyre-(5-metyl- 2- okso- 1, 3- dioksol- 4- yl) metylester ;[3S-[3a(Z),43]]-[[3-[[(2-amino-4-tiazolyl)(metoksyimino)-acetyl]amino]-4-metyl-2-okso-1-azetidinyl]oksy]eddiksyre-natriumsalt (0,95 g, se eksempel 18) ble løst i 25 ml dimetylformamid, avkjølt til 0°C og tilsatt 0,38 g 1,8-diazabicyklo-[5.4.0]undek-7-en og deretter 0,83 g 5-(brommetyl)-2-okso-4-fenyl-1,3-dioksol. Etter omrøring i 4 timer, ble dimetylformamidet fjernet under vakuum og residuet løst i etylacetat, vasket med iskaldt vann, natriumbikarbonat-oppløsning og salt-oppløsning, tørket (MgSO^) og inndampet. Residuet ble løst i etylacetat. Ved tilsetning av petroleter utfeltes tittelforbindelsen som et amorft faststoff. ;Eksempel 87 ;[3S-[3a (Z) ,4 |3] ]-[ [3-[ [ (2-amino-4-tiazolyl) (metoksyimino) - acetyl]amino]-4-metyl-2-okso-1-azetidinyl]oksy]eddiksyre-( acetyloksy) metylester ;Til en løsning av [3S-[3a(Z),43]]-[[3-[[(2-amino-4-tiazolyl)(metoksyimino)acetyl]amino]-4-metyl-2-okso-1-azetidinyl]oksy]eddiksyre-natriumsalt (3,2 g; se eksempel 18) ;i 50 ml tørr dimetylformamid ble under omrøring, dråpevis tilsatt 1,86 g klormetylacetat, hvorpå omrøringen ble fortsatt i 3 dager. Løsningsmidlet ble inndampet under vakuum og residuet tatt opp i etylacetat, vasket suksessivt med iskaldt vann, iskald vandig natriumbikarbonat og iskald saltoppløsning og deretter tørket over CaSO^. Etter filtrering og fjerning av løsningsmidlet under vakuum, ble residuet kromatografert på kiselgel med etylacetat som eluent, hvorved 1,08 g av tittelforbindelsen ble oppnådd, dekomp >74°C. ;Eksempel 88 ;[3S-[3a(Z),43]]-[[3-[[(2-amino-4-tiazolyl)(metoksyimino)-acetyl]amino]-4-(azidometyl)-2-okso-1-azetidinyl]oksy]-eddiksyre- kaliumsalt, ;A) 5-( klormetyl)- 4, 5- dihydro- 4- oksazolkarboksamid;114 g kloracetaldehyd-monohydrat og 84 g isocyanoacetamid ble løst i 1000 ml metanol. Blandingen ble avkjølt til 0-3°C ;og en løsning av 38 g 1,8-diazabicyklo[5.4.0]undek-7-en i 200 ml metanol bie tilsatt under omrøring. Ved denne temperatur ble omrøringen fortsatt i 30 minutter og deretter i 1 time etter fjerning av kjølebadet. Løsningsmidlet ble fjernet under vakuum og residuet tilbakeløpsbehandlet 2 ganger, hver gang med 1000 ml etylacetat. De kombinerte varme ekstrakter ble behandlet med aktivkull og i varm tilstand filtrert og inndampet, hvorved tittelforbindelsen ble oppnådd som et krystallinsk residuum som etter omkrystallisering fra etylacetat, smeltet ved 110-112°C. ;B) 4- klor- DL- threoninamid- hydroklorid ;5-(klormetyl)-4,5-dihydro-4-oksazolkarboksamid ble løst i 1500 ml 2N saltsyre og oppvarmet til 50°C i 2 timer. Saltsyren ble fjernet under vakuum og residuet utgnidd med isopropanol, hvorved tittelforbindelsen ble oppnådd som brun-aktige krystaller; utbytte 133,9 g. ;C) 4- klor- DL- threonin;70 g 4-klor-DL-threoninamid-hydroklorid ble løst i;350 ml vann. Løsningen ble sendt gjennom en søyle fylt med 1,8 kg Amberlyst 15. Søylen ble vasket med vann for å fjerne saltsyren. Materialet ble deretter fjernet fra søylen og under omrøring oppvarmet til 60°C i 5 timer. Etter avkjøling ble resinet anbrakt i søylen igjen og deretter eluert med en løsning av 5% trikloreddiksyre i vann. Fraksjoner som inneholdt DL-klor-threonin ble samlet opp, inndampet til et lite volum og ekstrahert 4 ganger med 4 00 ml porsjoner eter for å fjerne trikloreddiksyren. Den vandige fase ble frysetørket og residuet løst i 200 ml isopropanol, hvorfra tittelforbindelsen utkrystallisertes (utbytte 27 g). En ytterligere produktfraksjon på 7 g ble oppnådd ved inndampning av moderluten, behandling av det oljeaktige residuum med eter, fjerning av eteren og ny behandling av det uløselige materiale med isopropanol . ;D) N-( t- butyloksykarbonyl)- 4- klor- DL- threonin;22 g 4-klor-DL-threonin ble suspendert i en blanding av 43 ml vann og 71 ml t-butanol. Ved tilsetning av 2N natrium-hydroksyd ble pH justert til 7,0 og blandingen tilsatt 34,3 g di-tert-butylpyrokarbonat og under omrøring holdt ved pH 7,5 ;i 3 timer. Opparbeidning av reaksjonsblandingen ga tittelforbindelsen i form av et sirupøst produkt. ;E) , N- ( t- butyloksykarbonyl) - 4- azido- DL- threonin;16,8 g N-(t-butyloksykarbonyl)-4-klor-DL-threonin ble løst i 170 ml metanol og 70 ml vann. Blandingens pH ble justert til 11 ved tilsetning av kaliumkarbonat (9,5 g) , hvorpå 13 g natriumazid ble tilsatt og pH holdt ved 11 i 24 timer (romtemperatur). Metanolen ble fjernet under vakuum og den vandige fase ekstrahert med etylacetat og justert til ;pH 2,5 ved tilsetning av fosforsyre. Den vandige fase ble ekstrahert 2 ganger til med etylacetat og de kombinerte organiske faser tørket (MgSO^) og inndampet til 16,5 g av den sirupøse tittelforbindelse. ;F) [[N 2-(t-butyloksykarbonyl)-4-azido-DL-threoninamido]-oksy] eddiksyre- difenylmetylester ;16,4 g N-(t-butyloksykarbonyl)-4-azido-DL-threonin ble løst i 250 ml tetrahydrofuran. Løsningen ble tilsatt 16,3 g (aminooksy)eddiksyre-difenylmetylester og 40 ml vann, etterfulgt av 0,9 7 g N-hydroksybenzotriazol og 13,1 g drcyklo-heksylkarbodiimid. Etter omrøring over natten ble den utfelte dicykloheksylurea frafiltrert. Filtratet ble inndampet under vakuum og det oljeaktige residuum løst i etylacetat, filtrert og vasket med natriumbikarbonat-løsning og saltoppløsning. Etter tørking (MgSO^) og inndampning av løsningsmidlet under vakuum, ble 36 g råprodukt i form av en olje oppnådd. Produktet ble renset ved kromatografi på kiselgel under eluering med en 70:30 blanding av diklormetan/etylacetat. ;G) [[N 2-(t-butyloksykarbonyl)-4-azido-O-(metylsulfonyl)-DL- threoninamido] oksy] eddiksyre- difenylmetylester ;6,5 g [[N 2-(t-butyloksykarbonyl)-4-azido-DL-threonin-amido]oksy]eddiksyre-difenylmetylester ble mesylert etter metoden beskrevet i eksempel 39B, hvorved 6,8 g av tittelforbindelsen ble oppnådd som en olje. ;H) (trans)-[[4-(azidometyl)-3-[(t-butyloksykarbonyl)amino]-2- okso- 1- azetidinyl3 oksy] eddiksyre- difenylmetylester ;6,8 g [[N 2-(t-butyloksykarbonyl)-4-azido-O-(metyl-sulf onyl) -DL-threoninamido3oksy3 eddiksyre-difenylmetylester ble cyklisert etter metoden beskrevet i eksempel 39C, hvorved 3,8 g av tittelforbindelsen ble oppnådd som en olje. ;I) (trans)-[[3-(amino-4-(azidometyl)-2-okso-1-azetidinyl]-oksy3 eddiksyre- trifluoracetatsalt ;3,8 g (trans)-[[4-(azidometyl)-3-[(t-butyloksykarbonyl)-amino]-2-okso-1-azetidinyl]oksy]eddiksyre-difenylmetylester ble løst i 3 ml anisol ved romtemperatur og avkjølt til -10°C. Ved denne temperatur ble det tilsatt 30 ml trifluoreddiksyre, ;hvoretter blandingen ble holdt ved -10°C i 30 minutter. Ved tilsetning av 70 ml eter, ble tittelforbindelsen utfelt (0,6 g). En ytterligere produktfraksjon på 0,6 g ble oppnådd ved inndampning av filtratet og behandling av det oljeaktige residuum med eter. ;J) [3S-[3oc(Z) ,43] ]-[ [3-[ [ (2-amino-4-tiazolyl) (metoksyimino) - acetyl]amino]-4-(azidometyl)-2-okso-1-azetidinyl]oksy]eddiksyre- kaliumsalt ;0,33 g (trans)-[[3-amino-4-(azidometyl)-2-okso-1-azetidinyl]oksy]eddiksyre-trifluoracetatsalt ble suspendert i 20 ml acetonitril og 0,6 ml N-metyl-N-trimetylsilyltrifluoracetamid tilsatt for å oppnå oppløsning etter 30 minutters omrøring. Løsningen ble avkjølt til 0°C og tilsatt 0,35 g (Z)-2-amino-a-(metoksyimino)-4-tiazoleddiksyre-N-hydroksy-benzotriazolester. Blandingen ble omrørt ved romtemperatur i 2,5 timer og 1 ml av en løsning av kalium-etylheksanoat tilsatt, hvorpå blandingen ble inndampet under vakuum til et lite volum. Ved tilsetning av eter, utfeltes tittelforbindelsen i form av 0,55 g råprodukt. Dette ble renset ved kromatografi på HP-20. Tittelforbindelsen ble eluert med vann/aceton (80:20); utbytte 95 mg. ;Eksempel 89 ;(trans)-[[3-(t-butyloksykarbonyl)-4-metyl-2-okso-1-azetidinyl]-oksy] ( metyltio) eddiksyre- metylester ;A) Brom( metyltio) eddiksyre- metylester;24,0 g (metyltio)eddiksyre-metylester, 32,8 g N-brom-succinimid og 100 mg 2,2'-azobis-(2-metylpropionitril) ble oppvarmet i 1 time til 60°C i 150 ml karbontetraklorid. Etter avkjøling og filtrering, ble løsningsmidlet fjernet under vakuum og residuet destillert, hvorved 26,8 g brom(metyltio)-eddiksyre-metylester ble oppnådd som en rød olje. ;B) (trans)-[[3-(t-butyloksykarbonyl)-4-metyl-2-okso-1-azetidinyl] oksy]( metyltio) eddiksyre- metylester ;2,16 g 3-[(t-butyloksykarbonyl)amino]-1-hydroksy-4-metyl-2-azetidinon og 2,20 g brom(metyltio)eddiksyre-metylester ble løst i 50 ml dimetylformamid. I løpet av et tidsrom på 3 timer ble 1,11 g trietylamin i 30 ml dimetylformamid tilsatt, og blandingen omrørt i 2 dager ved romtemperatur. Løsningsmidlet ble fjernet under vakuum og residuet suspendert i 20 ml etylacetat. Etter frafiltrering av ammoniumsaltet, ble løsningen konsentrert og kromatografert på kiselgel med etylacetat som eluent, hvorved 2,0 g produkt ble oppnådd i form av en olje. ;IR (film): 1780, 1745, 1710 cm"<1>. ;NMR (DMSO-dg): 6 = 1,38 (s, 9H), 2,22 (s, 3H), 3,76 (s, 3H), 5,63 og 5,66 (2s, 1H), 7,60 (br, d, 1H). ;Eksempel 90 ;[3S-[3a(Z),43]]-t[3-[[(2-amino-4-tiazolyl)(metoksyimino)-acetyl]amino]-4-metyl-2-okso-1-azetidinyl]oksy]eddiksyre-1-metyletylester ;A) (3S-trans)-3-(t-butyloksykarbonylamino)-1-hydroksy-4-metyl- 2- azetidinon ;10,5 g (3S-trans)-3-(t-butyloksykarbonylamino)-1-benzyloksy-4-metyl-2-azetidinon ble løst 250 ml metanol og hydrogenert med 1,43 g palladium-på-karbon (10%) som katalysator. Etter 45 minutter ble katalysatoren frafiltrert og filtratet inndampet under vakuum. Den krystallinske tittelforbindelse ble tørket (vakuumeksikator) ved romtemperatur, hvorved 7,3 g av tittelforbindelsen ble oppnådd; ;smp. 161-16 2°C dekomp.;B) (3S-trans)-[[3-[(t-butyloksykarbonyl)amino]-4-metyl-2- okso- 1- azetidinyl] oksy] eddiksyre- 1- metyletylester ;11,3 g trietylamin ble dryppet inn i en løsning av 19,5 g (3S-trans)-3-(t-butyloksykarbonylamino)-1-hydroksy-4-metyl-2-azetidinon og 14,8 g kloreddiksyre-1-metyletylester i 4 00 ml tørr dimetylformamid, hvorpå blandingen ble omrørt ved rom- ;temperatur i 3 dager. Trietylamin-hydroklorid ble frafiltrert og løsningsmidlet avdestillert under vakuum ved 35°C. Den gjenværende olje ble tatt opp i eter og ekstraktet anbrakt i kjøleskap i ca 2 timer og deretter filtrert, hvorpå eteren igjen ble fordampet under vakuum. Den resulterende oljeaktige tittelforbindelse (30 g) som inneholdt ca 2 g forurensninger, ;ble benyttet i neste trinn uten ytterligere opprensning.;C) (3S-trans)-[[3-amino-4-metyl-2-okso-1-azetidinyl]oksy]-eddiksyre- 1- metyletylester- trifluoracetat ;30 g urenset (3S-trans)-[[3-[(t-butyloksykarbonyl)-amino]-4-mety1-2-okso-1-azetidinyl]oksy]eddiksyre-1-metyletyl- ;ester ble løst i en blanding av 230 ml trifluoreddiksyre og 23 ml anisol ved -10°C. Omrøringen ble fortsatt ved -2°C i 30 minutter. Etter inndampning av trifluoreddiksyreløsningen under vakuum ved lav temperatur (10-20°C), ble det oljeaktige residuum løst i 350 ml vannfri eter, hvorpå utkrystallisering av trifluoracetatsaltet begynte umiddelbart. Plassering av eterblandingen i kjøleskap førte til øket utbytte. Etter frafiltrering, ble tittelforbindelsen vasket 2 ganger med vannfri eter og deretter med petroleter (40-60°C), hvorved det etter tørking i eksikator (P20^) ble oppnådd 18 g produkt; ;smp. 12 5,5°C.;D) [3S-[3a(Z),43]]-[[3-[[(2-amino-4-tiazolyl)(metoksyimino)-acetyl]amino]-4-metyl-2-okso-1-azetidinyl]oksy]eddiksyre-1-metyletylester ;Under omrøring ble 5,8 g vannfri trietylamin løst i 50 ml vannfri dimetylformamid, dråpevis tilsatt til en løsning av ;17,5 g (3S-trans)-[[3-amino-4-metyl-2-okso-1-azetidinyl]-oksy]eddiksyre-1-metyletylester-trifluoracetat (0,053 mol) og ;16,9 g (Z)-2-amino-a-(metoksyimino)-4-tiazoleddiksyre-1-hydroksybenzotriazolester (0,053 mol) i 200 ml dimetylformamid avkjølt til 0°C. Etter 2 timer (ved fullført trietylamin-tilsetning) fikk temperaturen av reaksjonsblandingen langsomt stige til 20°C. Ved denne temperatur ble omrøringen fortsatt i ytterligere 4 timer. Dimetylformamid ble fjernet under vakuum og den gjenværende olje tatt opp i etylacetat og rystet med ;iskald vandig natriumbikarbonat (1N) og deretter med iskaldt;vann. Etylacetatlaget som ble tørket med Na2S0^, ble inndampet under vakuum til 18,8 g av tittelforbindelsen. Kromatografi på kiselgel med tetrahydrofuran/etylacetat (1:1) ga et rent produkt; smp. 87-95°C dekomp. ;Eksempel 91 ;[3S-[3a(Z),43]]-[[3-[[(2-amino-4-tiazolyl)(metoksyimino)-acetyl]amino]-4-mety1-2-okso-1-azetidinyl]oksy]eddiksyre-2-propenylester ;A) (3S-trans)-t[3-[(t-butyloksykarbonyl)amino]-2-metyl-4-okso- 1- azetidinyl] oksy] eddiksyre- 2- propenylester ;En løsning av 17,3 g (3S-trans)-3-(t-butyloksykarbonyl-amino) -1 -hydroksy-4-metyl-2-azetidinon og 12,9 g kloreddiksyre-2-propenylester i 350 ml tørr dimetylformamid fikk stå i 4 dager ved romtemperatur og ble deretter opparbeidet som beskrevet i eksempel 90B. Utbytte 25,5 g rå ester. ;B) (3S-trans)-[[3-amino-4-metyl-2-okso-1-azetidinyl]oksy]-eddiksyre- 2- propenylester- trifluoracetat ;25,5 g av den rå (3S-trans)- f[3-[(t-butyloksykarbonyl)-amino]-4-mety1-2-okso-1-azetidinyl]oksy]eddiksyre-2-propeny1-ester ble tilsatt til en omrørt blanding av 200 ml trifluoreddiksyre og 20 ml anisol avkjølt til -10°C. Etter omsetning i 25 minutter ved -2°C, ble overskuddet av trifluoreddiksyre fjernet under vakuum ved en temperatur som varierte fra 20 til 25°C. Det oljeaktige residuum ble tatt opp i 250 ml vannfri eter og anbrakt i kjøleskap. Den utkrystalliserte tittelforbindelse ble deretter frafiltrert, vasket 2 ganger med vannfri eter og tilslutt med petroleter (40-60°C) og tørket i en eksikator over P2°5'hvilket resulterte i 17,7 g produkt; smp. 112-113°C. ;C) [3S-[3a(Z),43]]-[[3-[[(2-amino-4-tiazolyl)(metoksyimino)-acetyl]amino]-4-metyl-2-okso-1-azetidinyl]oksy]eddiksyre-2- propenylester ;Til en omrørt blanding av 17,4 g (3S-trans)-[[3-amino-4-mety1-2-okso-1-azetidinyl]oksy]eddiksyre-2-propenylester-trifluoracetat (0,053 mol) og 16,9 g (Z)-2-amino-a-(metoksy imino)-4-tiazoleddiksyre-1-hydroksybenzotriazolester i 200 ml dimetylformamid, avkjølt til 0°C, ble det porsjonsvis tilsatt 5,8 g trietylamin i 40 ml vannfri dimetylformamid. Løsningens temperatur ble deretter holdt ved 5°C i 1 time og deretter ved 10°C i 2 timer, hvorpå blandingen fikk stå ved romtemperatur over natten. Opparbeidningen ble foretatt som beskrevet i eksempel 90D. Utbytte 18 g; smp. 75-80°C dekomp. ;Eksempel 92 ;[3S-[3a(Z),43]]~[[3-[[(2-amino-4-tiazolyl)(metoksyimino)-acetyl]amino]-4-mety1-2-okso-1-azetidinyl]oksy]eddiksyre-2- propynylester ;A) (3S-trans)-[[3-[(t-butyloksykarbonyl)amino]-4-metyl-2-okso- 1- azetidinyl] oksy] eddiksyre- 2- propynylester ;Ved å følge fremgangsmåten i eksempel 91A, men med klor-eddiksyre-2-propynylester (1,7 g) i stedet for kloreddiksyre-2-propenylester, ble det oppnådd 2,2 g av tittelforbindelsen i form av en olje som ble benyttet i neste trinn uten rensing. ;B) (3S-trans)-[[3-amino-4-mety1-2-okso-1-azetidinyl]oksy]-eddik syre- 2- propynylester- trifluoracetat ;Fjerning av beskyttelsesgruppen av den ovenfor oppnådde forbindelse (2,2 g) ble oppnådd med trifluoreddiksyre/anisol (25 ml/2,5 ml) ved bruk av fremgangsmåten i eksempel 92B. Utbytte 1,7 g; smp. 106-107°C. ;C) [3S-[3a(Z),43]]-t[3-[[(2-amino-4-tiazolyl)(metoksyimino) acetyl]amino]-4-metyl-2-okso-1-azetidinyl]oksy]-eddiksyre- 2- propynylester ;1,6 g (3S-trans)-[[3-amino-4-metyl-2-okso-1-azetidinyl]-oksy]eddiksyre-2-propynylester-trifluoracetat ble koblet med 1,6 g (Z)-2-amino-a-(metoksyimino)-4-tiazoleddiksyre-1-hydroksybenzotriazolester som beskrevet i eksempel 92C. Kromatografi på kiselgel med tetrahydrofuran/eter (1:1) førte til 1,1 g av tittelforbindelsen; smp. 69-75°C dekomp. ;Eksempel 9 3 ;[3S-[3a(Z),43]]-[[3-[[(2-amino-4-tiazolyl)(metoksyimino)-acetyl]amino]-4-metyl-2-okso-1-azetidinyl]oksy]eddiksyre-propylester ;A) (3S-trans)-[[3-[(t-butyloksykarbonyl)amino]-4-metyl-2-okso- 1- azetidinyl] oksy] eddiksyre- propylester ;Ved å følge fremgangsmåten i eksempel 91A, men med klor-eddiksyre-propylester (3,0 g) i stedet for kloreddiksyre-2-propenylester, ble 4,2 g av tittelforbindelsen oppnådd; ;smp. 72°C.;B) (3S-trans)-[[3-amino-4-metyl-2-okso-1-azetidinyl]oksy]-eddiksyre- propylester- trifluoracetat ;Behandling av foregående ester (4,2 g) med 50 ml trifluoreddiksyre og 5 ml anisol, som angitt i eksempel 91B, førte til 3,3 g av tittelforbindelsen. ;C) [3S-[3a(Z),43]]~[[3-[[(2-amino-4-tiazolyl)(metoksyimino)-acetyl]amino]-4-mety1-2-okso-1-azetidinyl]oksy]eddiksyre-propylester ;4,88 ml MSTFA (95%) (2,5 mmol) ble tilsatt til en suspensjon av 3,3 g (3S-trans)-[[3-amino-4-metyl-2-okso-1-azetidinyl]oksy]eddiksyre-propylester-trifluoracetat i 60 ml tørr acetonitril ved 0°C. Omrøring ble fortsatt inntil tri-fluoracetatet var gått i oppløsning. Den klare løsning fikk stå over natten og etter fordampning av acetonitril under vakuum, ble den gjenværende olje (3,39 g) løst i 40 ml tørr tetrahydrofuran og tilsatt 2,96 g (Z)-2-amino-a-(metoksyimino)-4-tiazoleddiksyre-1-hydroksybenzotriazolester (8,44 mmol) og blandingen omrørt i 4 timer ved romtemperatur. Løsningsmidlet ble fjernet under vakuum ved 30°C og residuet tatt opp i etylacetat, rystet med iskald vandig natriumbikarbonat (1N) ;og deretter med isvann. Etylacetatlaget ble tørket med Na2SO^og tittelforbindelsen (4 g olje) kromatografert på kiselgel med etylacetat. Utbytte 3,1 g; smp. 68-71°C dekomp. ;Eksempel 94 ;[3S-[3a(Z),43]]-[[3-[[(2-amino-4-tiazolyl)(metoksyimino)-acetyl]amino]-4-metyl-2-okso-1-azetidinyl]oksy]eddiksyre-2- kloretylester ;A) (3S-trans)-[[3-[(t-butyloksykarbonyl)amino]-4-metyl-2- okso- 1- azetidinyl] oksy] eddiksyre- 2- kloretylester ;Ved å følge fremgangsmåten i eksempel 91A, men med klor-eddiksyre-2-kloretylester (4,32 g) i stedet for kloreddiksyre-2-propenylester, ble det oppnådd 5,2 g av tittelforbindelsen (etylacetat/eter 1:1 ble benyttet som eluent ved kromatografi på kiselgel). ;B) (3S-trans)-[[3-amino-2-metyl-4-okso-1-azetidinyl]oksy]-eddiksyre- 2- kloretylester- trifluoracetat ;Ved bruk av trifluoreddiksyre og anisol (som beskrevet i eksempel 91B) ble tittelforbindelsen fremstillet fra det foregående t-butyloksykarbonyl-beskyttede aminoderivat• ;Utbytte 4,19 g.;C) [2S-[2a,33(Z)]]-[[3-[[(2-amino-4-tiazolyl)(metoksyimino)-acetyl]amino]-2-mety1-4-okso-1-azetidinyl]oksy]eddiksyre-2- kloretylester ;2,0 g (3S-trans)-[[3-amino-4-metyl-2-okso-1-azetidinyl] - oksy]eddiksyre-2-kloretylester-trifluoracetat ble koblet med 1,89 g (Z)-2-amino-a-(metoksyimino)-4-tiazoleddiksyre-1-hydroksybenzotriazol som beskrevet i eksempel 91C, hvorved 1,66 g av tittelforbindelsen ble oppnådd (tetrahydrofuran/eter 1:1) ble benyttet som eluent ved kromatografi på kiselgel); smp. 84-85°C dekomp. ;Eksempel 9 5 ;[3S-[3a(Z),4 3]]-[[3-[[(2-amino-4-tiazolyl)(metoksyimino)-acetyl]amino]-4-mety1-2-okso-1-azetidinyl]oksy]eddiksyre-cykloheksylester ;(3S-trans)-[[3-[(t-butyloksykarbonyl)amino]-4-metyl-2-okso-1-azetidinyl]oksy]eddiksyre-cykloheksylester (2,23 g) fremstillet analogt med fremgangsmåten i eksempel 91A, ble løst i en oppløsning av 25 ml trifluoreddiksyre og 2,5 ml ;anisol ved -10°C. Blandingen ble inndampet under vakuum 25 minutter senere og residuet omrørt med eter, frafiltrert og tørket over ?2^5rarveløse krystaller av (3S)-[[3-amino-4-mety1-2-okso-1-azetidinyl]oksy]eddiksyre-cykloheksylester-trifluoracetatsalt (utbytte 1,53 g). Saltet (1,5 g) ble suspendert i 30 ml acetonitril og ved 0°C tilsatt MSTFA ;(2,37 ml) og løsningen hensatt over natten. Etter inndampning under vakuum, ble residuet (1,75 g) løst i tørr tetrahydrofuran (25 ml), og tilsatt 1,4 g (Z)-2-amino-a-(metoksyimino)-4-tiazoleddiksyre-1-hydroksybenzotriazolester og blandingen omrørt ved romtemperatur i 4 timer. Tetrahydrofuran ble fjernet under vakuum ved 30°C og residuet tatt opp i eter, vasket med iskald vandig NaHCO^(1N) og 2 ganger med kaldt vann. Det tørkede etylacetatlaget ble fordampet under vakuum og den resulterende olje (2,14 g) kromatografert på kiselgel med etylacetat, hvorved 1,58 g tittelforbindelse ble oppnådd; ;smp. 8 5-90°C dekomp.;Eksempel 96 ;[3S-[3a(Z),43]]-[[3-[[(2-amino-4-tiazolyl)(metoksyimino)-acetyl]amino]-4-metyl-2-okso-1-azetidinyl]oksy]eddiksyre-cyklopentylester ;Ved å følge fremgangsmåten i eksempel 95, men med (3S-trans)-[[3-[(t-butyloksykarbonyl)amino]-4-metyl-2-okso-1-azetidinyl]oksy]eddiksyre-cyklopentylester i stedet for (3S-trans)-[[3-[(t-butyloksykarbonyl)amino]-4-metyl-2-okso-1- azetidinyl]oksy]eddiksyre-cykloheksylester, ble tittelforbindelsen oppnådd; smp. 90-95°C dekomp. ;Eksempel 9 7 ;[3S-[3a(Z),43]]-[[3-[[(2-amino-4-tiazolyl)(metoksyimino)-acetyl]amino]-4-metyl-2-okso-1-azetidinyl]oksy]eddiksyre-cyklopentylmetylester ;(3S-trans)-[[3-[(t-butyloksykarbonyl)amino]-4-metyl-2- okso-1-azetidinyl]oksy]eddiksyre-cyklopentyImetylester, ;som kan oppnås fra (3S-trans)-3-(t-butyloksykarbonylamino-1-hydroksy-4-metyl-2-azetidinon og kloreddiksyre-cyklopentyl- ;metylester, ble befridd for beskyttelsesgruppen og koblet til tittelforbindelsen ved å følge fremgangsmåten beskrevet i ekempel 90B til 90D; smp. 73-80°C dekomp. ;Eksempel 98 ;[3S-[3a(Z),43]]-[[3-t[(2-amino-4-tiazolyl)(metoksyimino)-acetyl]amino]-4-mety1-2-okso-1-azetidinyl]oksy]eddiksyre-2, 2- dimetylpropylester ;(3S-trans)-[[3-[(t-butyloksykarbonyl)amino]-4-metyl-2-okso-1-azetidinyl]oksy]eddiksyre-2,2-dimetylpropylester ble omdannet via det korresponderende trifluoracetatsalt til tittelforbindelsen (smp. 74-76°C dekomp) ved å benytte fremgangsmåten i eksempel 91A til 91C. ;Eksempel 99 ;[3S-[3a(Z),43]]-[[3-[[(2-amino-4-tiazolyl)(metoksyimino)-acety1]amino]-4-metyl-2-okso-1-azetidinyl]oksy]eddiksyre-2- etylbutylester ;Ved å følge fremgangsmåten i eksempel 91A til 91C, ble (3S-trans)-[[3-[(t-butyloksykarbonyl)amino]-4-metyl-2-okso-1-azetidinyl]oksy]eddiksyre-2-etylbutylester omdannet via trifluoracetatsaltet til tittel-esteren; smp. 56-60°C dekomp. ;Eksempel 100 ;[3S-[3a(Z),43]]-[[3-[[(2-amino-4-tiazolyl)(metoksyimino)-acetyl]amino]-4-mety1-2-okso-1-azetidinyl]oksy]eddiksyre-2, 2, 2- trifluoretylester ;Ved å følge fremgangsmåten i eksempel 90, ble (3S-trans)-[[3-[(t-butyloksykarbonyl)amino]-4-metyl-2-okso-1-azetidinyl]-oksy]eddiksyre-2,2,2-trifluoretylester deacylert til det korresponderende trifluoracetatsalt og deretter koblet med (Z)-2-amino-a-(metoksyimino)-4-tiazoleddiksyre-1-hydroksy-benzotriazolester til tittelforbindelsen; smp. 75-81°C dekomp. ;Eksempel 101 ;[3S-[3a(Z),43]]-[[3[[(5-amino-1,2,4-tiadiazol-3-yl)(metoksyimino) acetyl] amino]- 4- mety1- 2- okso- 1- azetidinyl] oksy] eddiksyre ;(3S-trans)-[[3-[(butyloksykarbonyl)amino]-4-metyl-2-okso-1-azetidinyl]oksy]eddiksyre-difenylmetylester (15 g; 34 mmol) ble løst i en løsning av 112 ml trifluoreddiksyre og 11,2 ml anisol ved -10°C. Blandingen ble inndampet under vakuum 10 minutter senere, hvorpå residuet ble omrørt med eter, frafiltrert og tørket over P2°5t:L1 7' 3 g krystaller av (3S)-[[3-amino-4-metyl-2-okso-1-azetidinyl]oksy]eddiksyre-trifluoracetatsalt. Saltet (7,3 g) ble suspendert i 30 ml tørr acetonitril, tilsatt MSTFA (3,34 ml) og røringen fortsatt i 1 time. Etter inndampning under vakuum ble residuet løst i tørr tetrahydrofuran, hvorpå (Z)-5-amino-1,2,4-tiadiazol-3-yl-a-(metoksyimino)eddiksyre-1-hydroksybenzotriazolester (2,0 g) ble tilsatt og blandingen omrørt over natten ved romtemperatur og inndampet under vakuum. Etter tilsetning av eter, ble det rå silylerte produkt dekomponert med 0,5 ml metanol. Det uløste produkt ble frafiltrert, oppløst i tetrahydrofuran og kromato-graf ert på kiselgel med etylacetat/eter 1:1, hvorved tittelforbindelsen ble oppnådd; smp. 165-166°C. ;Eksempel 102 ;[3S-[3a(Z),43]]-[[3-[[(5-amino-1,2,4-tiadiazol-3-yl)(metoksyimino) acetyl]amino]-4-metyl-2-okso-1-azetidinyl]oksy]eddiksyre- 1- metyletylester ;1,35 g (3S-trans)[[3-amino-4-metyl-2-okso-1-azetidinyl]-oksy]eddiksyre-1-metyletylester-trifluoracetat (4,1 mmol) ble suspendert i 25 ml tørr acetonitril. MSTFA (2,28 ml) ble tilsatt ved 0°C, hvorpå røringen ble fortsatt i 3 0 minutter og løsningen hensatt over natten ved romtemperatur. Etter inndampning under vakuum, ble residuet (1,92 g) løst i 13 ml tørr tetrahydrofuran, tilsatt (Z)-5-amino-1,2,4-tiadiazol-3-yl-a-(metoksyimino)eddiksyre-1-hydroksybenzotriazolester (1,75 g) og blandingen omrørt over natten ved romtemperatur og inndampet under vakuum. Residuet ble tatt opp i etylacetat, vasket med iskald vandig NaHCO^(1N) og deretter med isvann. ;Etylacetatlaget ble tørket med Na2S04 og kromatografert på kiselgel med etylacetat som eluent. Utbytte av tittelforbindelsen var 1,10 g; smp. 83-85°C. ;Eksempel 103 ;[3S-[3a(Z),43]]-[[3-[[(6-amino-2-pyridinyl)(metoksyimino)-acetyl]amino]-4-mety1-2-okso-1-azetidinyl]oksy]eddiksyre-mononatriumsålt ;Ved å følge fremgangsmåten i eksempel 101, men med (Z)-6-amino-2-pyridinyl-a-(metoksyimino)eddiksyre-1-hydroksy-benzotriazolester i stedet for (Z)-5-amino-1,2,4-tiazdl-3-yl-a-(metoksyimino)eddiksyre-1-hydroksybenzotriazolester, ble den fri syre av tittelforbindelsen oppnådd. Denne ble suspendert i iskaldt vann, pH justert til 6,5 med 1N natrium-hydroksyd og den klare løsning frysetørket, hvorved saltet ble oppnådd; smp. 14 0°C dekomp. ;Eksempel 104 ;(3S-trans)-[[3-[[[(2,6-diklor-4-pyridinyl)tio]acetyl]amino]-4- metyl- 2- okso- 1- azetidinyl] oksyJeddiksyre- mononatriumsalt ;Ved å følge fremgangsmåten i eksempel 103, men med 2,6-diklor-4-pyridinyltioeddiksyre-4-nitrofenylester i stedet for (Z)-6-amino-2-pyridinyl-a-(metoksyimino)eddiksyre-1-hydroksy-benzotriazolester , ble tittelforbindelsen oppnådd; ;smp. 9 7-100°C dekomp.;Eksempel 105 ;[3S-[3a(Z),43]]-[[3-[[(2-amino-4-tiazolyl)(metoksyimino)-acetyl]amino]-4-mety1-2-okso-1-azetidinyl]oksy]eddiksyre-1-[[( cykloheksyloksy) karbonyl] oksy] etoksyester ;[3S-[3a(Z),43]]-[[3-[[(2-amino-4-tiazolyl)(metoksyimino)-acetyl]amino]-4-metyl-2-okso-azetidinyl]oksy]eddiksyre-mono-kaliumsalt (0,40 g) ble løst i 10 ml tørr dimetylformamid. a-kloretyl-cyklopentylkarbonat (0,20 g) og 0,083 g kaliumjodid ble tilsatt ved romtemperatur og omrørt ved romtemperatur i 2 dager. Løsningsmidlet ble inndampet under vakuum og residuet ;tatt opp i etylacetat, vasket suksessivt med vann, 1N NaHCO^-løsning, vann og deretter tørket (Na2S04>. Etter fjerning av løsningsmidlet under vakuum, ble den resulterende olje (0,34 g) renset ved kromatografi på kiselgel med en blanding av tetra-hydrof uran/eter (1:1) som eluent, hvorved 0,31 g oljeaktig tittelforbindelse, som krystalliserte etter behandling med vann, ble oppnådd; smp. 85-90°C dekomp. ;Eksempel 106 ;[3S-[3a(Z) ,43]]-[[3-[[(2-amino-4-tiazolyl) (metoksyimino)-acetyl]amino]-4-mety1-2-okso-1-azetidinyl]oksy]eddiksyre-1-[( etoksykarbonyl) oksy] etylester ;Ved å følge fremgangsmåten i eksempel 105, men med a-jodetyl-etylkarbonat i stedet for a-kloretyl-cyklopentyl-karbonat, ble tittelforbindelsen oppnådd; smp.120-125°C dekomp. ;Eksempel 107 ;[3S-[3a(Z),43]]-t[[[3-[[(2-amino-4-tiazolyl)(metoksyimino)-acetyl]amino]-4-metyl-2-okso-1-azetidinyl]oksy]acetyl]oksy]-eddiksyre- 1, 1- dimetyletylester ;Til en løsning av [3S-[3a(Z),43]]-tt3-[[(2-amino-4-tiazolyl)(metoksyimino)acetyl]amino]-4-mety1-2-okso-1-azetidinyl]oksy]eddiksyre-natriumsalt i 50 ml tørr dimetylformamid ble det dråpevis tilsatt 4,14 g t-butyljodacetat. Omrøring ble fortsatt ved romtemperatur i 3 timer. Løsnings-midlet ble fordampet under vakuum ved romtemperatur og residuet tatt opp i etylacetat, vasket suksessivt med iskaldt vann, iskald vandig NaHCO^og iskald saltoppløsning og deretter tørket over CaSO^. Etter filtrering og fjerning av løsningsmidlet under vakuum, ble residuet kromatografert på kiselgel med etylacetat som eluent, hvorved 2,9 g av tittelforbindelsen ble oppnådd; smp. 77°C dekomp. ;Eksempel 108 ;[3S[3ot(Z) ,4a] ]-[ [ 3-[ [ (2-amino-4-tiazolyl) (metoksyimino) - acetyl]amino]-4-metyl-2-okso-1-azetidinyl]oksy]eddiksyre-mononatriumsalt ;En løsning av 0,33 g trietylamin i 5 ml tørr dimetylformamid ble dryppet inn i en løsning av 0,33 g (3S-cis)-[(3-amino-4-mety1-2-okso-1-azetidinyl)oksy]eddiksyre-trifluoracetatsalt og 0,35 g (Z)-2-amino-2-(metoksyimino)-4-tiazol-eddiksyre-1-hydroksybenzotriazolester i 20 ml dimetylformamid ved 0°C, hvoretter omrøringen ble fortsatt i 3 timer ved romtemperatur. Løsningsmidlet ble deretter fordampet under vakuum og residuet suspendert i 10 ml n-butanol og tilsatt en løsning av 0,55 g natrium-2-etylheksanoat i 10 ml n-butanol. Blandingen ble omrørt i 4 timer ved romtemperatur. Presipitatet ble frafiltrert under sug, vasket med n-butanol og eter og deretter tørket under vakuum over P2<")5*Etter kromatografi (omvendt fase) på HP-20 resin med vann som eluent, etterfulgt av frysetørking av passende fraksjoner, ble tittelforbindelsen oppnådd; utbytte 0,14 g; dekomp. >170°C. In the case of the preferred 3-lactams of formula I, the structural formulas are drawn so as to show the stereochemical conditions at the chiral center in the 3-position. Following the nomenclature convention, compounds of formula I where 1*2 is hydrogen have the S configuration and compounds of formula I where R- is methoxy have the R configuration. The invention also encompasses racemic mixtures containing the above-described 3-lactams. ;3-lactam with a ; (or an ester or salt thereof) in the 1-position of the 3-lactam nucleus and an acylamino substituent in the 3-position, has an effect against a number of gram-negative and gram-positive organisms. ; (or an ester or salt thereof) is essential for the activity of these compounds. The compounds according to the invention can be used as agents for combating bacterial infections (including infections in the urinary tract and respiratory organs) in mammals such as domestic animals (e.g. dogs, cats, cattle, horses and the like) and humans. For combating bacterial infections, the compounds are given in amounts of 1.4-350 mg/kg/day, preferably 14-100 mg/kg/day. All administration methods that have been used to deliver penicillins and cephalosporins to the site of infection also come into consideration for the new 3-lactam family. These include oral, intravenous, intramuscular and suppository administration. The 3-lactams according to the invention can be prepared starting from an amino acid with the formula: ; If is hydrogen, the amino group is first protected with one of the classic protecting groups (eg t-butoxycarbonyl, benzyloxycarbonyl, o-nitrophenylsulfenyl, etc), whereby a compound of formula is obtained: ; where represents an amino or nitrogen protecting group. In formula III, and elsewhere in this specification, the symbol "A^" denotes a nitrogen or amino protecting group. For certain products of formula I, the desired acyl group "R^" can be used as the protecting group "A^" and thus introduced at the start of the reaction sequence. The carboxyl group in a protected amino acid of formula III or the corresponding compound where R^ is acyl is then reacted with an amine of formula: ; In formula IV, and in the rest of the description, the symbol "Y" shows i.a. to benzyl, trityl, pivaloyl, -CH2CH(NHA2)CO2alkyl, t-butyl, p-nitrobenzyl, benzhydryl, 2-cyanoethyl, 2-trimethyl-silylethyl, trichloroethyl and p-anisyl (where the symbol "A2" refers to a nitrogen- protective group). The reaction takes place in the presence of a coupling agent such as 1-ethyl-3-(3-dimethylamino-propyl)carbodiimide or dicyclohexylcarbodiimide and leads to a compound of formula: ; The hydroxyl group in a compound of formula V is converted into a leaving group, e.g. using a classical reagent such as methanesulfonyl chloride (methanesulfonyl is referred to in the following as "Ms"). ;The fully protected compound of formula:; is cyclized by treatment with a base, e.g. potassium carbonate. The reaction is preferably carried out in an organic solvent such as acetone, under reflux conditions and leads to a compound of formula VII: ; Alternatively, cyclization of a compound of formula V can be achieved without first converting the hydroxyl group into a leaving group. Treatment of a compound of formula V with triphenylphosphine and diethyl azodicarboxylate or carbon tetrachloride leads to a compound of formula VII. Both of these cyclization methods for compound V lead to inversion of the stereochemical relationships in the R^ and R^ substituents. ;By selective reduction of a compound of formula VII (by catalytic hydrogenation if Y is benzyl or by treatment with a base such as sodium sulphide or sodium hydroxide if Y is pivaloyl or with DB.U if Y is ;-CH^CH(NHA2) C02alkyl, the corresponding compound of formula is obtained: ; Alkylation of a hydroxamic acid of formula VIII with an activated and optionally protected form of a compound of formula: ; can be achieved by first generating the anion of the hydroxamic acid by means of a suitable base and then reacting the resulting compound with an activated form of an acetic acid derivative of formula IX. Activated and protected forms of compound IX have the formula: where Yj. is a suitable leaving group, such as a halogen atom (preferably bromine or chlorine), a mesylate or triflate group or one of the other well-known leaving groups, and Y^ is hydrogen or an ester group. The alkylation is described here as a 2-step reaction, but both steps can be carried out simultaneously. resulting product has the formula: ; Removal of the protective group from the 3-amino substituent in a compound of formula X can be achieved by known techniques. If the protecting group is, for example, t-butoxycarbonyl, the amino group can be released with the help of trifluoroacetic acid. If the protecting group is benzyloxycarbonyl, catalytic (eg palladium-on-carbon) hydrogenation can be used. If the protecting group is o-nitrophenylsulfenyl, a combination of p-toluenesulfonic acid and p-thiocresol can be used. After removal of the protecting group, the compound has the formula: ; and this intermediate plays a key role in the preparation of the compounds according to the invention, and also forms part of it. ;Well-known acylation techniques can be used to convert a compound of formula XI into the corresponding compound of formula: ; where is acyl. For example, this technique includes reaction with a carboxylic acid (R^-OH) or a corresponding carboxylic acid halide or carboxylic anhydride. The reactions with a carboxylic acid proceed most easily in the presence of a carbodiimide such as dicyclohexylcarbodiimide and a compound which has the ability to form a reactive intermediate in situ, e.g. N-hydroxybenzotriazole or N-hydroxysuccinimide. In cases where the acyl group (R^) contains reactive (e.g. amino or carboxyl) groups, it may be necessary that these functional groups are first protected, after which the acylation reaction is carried out and the resulting product is finally freed of the protective group. Removal of the protecting group from the carboxylic acid, followed by possible esterification, leads to the desired product of formula I. Esterification methods are illustrated in the examples. Alternative methods exist for converting an intermediate of formula X into a product of formula I. For example, a compound of formula X can be reacted with N-methyl-N-trimethylsilyl-trifluoroacetamide (MSTFA) and a silane, such as . iodotrimethylsilane, to cleave off the "AI" and "Y D" groups and give the corresponding 3-trimethylsilylamino compound which can be acylated according to the methods described above. The products of formula I, where R is methoxy, can also be prepared from the corresponding compound of formula VII where R 2 is hydrogen. Halogenation (preferably chlorination) of the amide nitrogen in a compound of formula VII leads to a compound of formula: ; Reagents and methods for N-chlorination of amides are known. Suitable reagents are, for example, tert-butyl hypochlorite, sodium hypochlorite and chlorine. The reaction can be carried out in an organic solvent (eg a lower alkanol such as methanol) or in a two-phase system (eg water/methylene chloride) in the presence of a base such as sodium borate decahydrate, preferably at reduced temperature. ;Reaction of a compound of formula XIII with a methoxylating agent, e.g. an alkali metal methoxide, leads to a compound (in combination with its enantiomers if R^ and R^ are equal, or XIII is a racemic mixture) of the formula: ; The reaction can be carried out in an organic solvent, e.g. a. polar organic solvent such as tetrahydrofuran, at reduced temperature. Alternatively, a compound of formula VII can be converted to compound XIV by a single-step method. The methoxylating agent is mixed below with a compound of formula VII, after which the N-chlorination reagent is added to the reaction mixture. The transfer of a compound of formula XIV to the desired product of formula I (or an ester thereof) can be achieved by means of the above-described methods for converting an intermediate product of formula XIV into a product according to the invention. An alternative process for the preparation of the compounds according to the invention comprises a more direct synthesis of the compounds of formula X. Reaction of an N-protected amino acid of formula III with a compound formed by reaction between a compound of formula IXa and N-hydroxyphthalimide, followed by reaction with hydrazine, leads to a compound of formula XV: ; By following the methods described above, the hydroxyl group in a compound of formula XV can be converted into a leaving group and the resulting compound cyclized to the corresponding compound X. The starting materials of formula II can be easily obtained by already known methods; see e.g. Synthesis, p. 216 (1979) and J. Org. Chem., 44:3967 (1979). The following tables show compounds according to the invention produced by means of the technique described above. The methodology is further illustrated for specific compounds in the examples that follow the tables. In the compounds shown in the tables, the oximes have the stereochemical syn form. ; ; Example 1 ;[3S(Z)]-[t 3-[[(2-amino-4-thiazolyl) (methoxyimino)-acetyl]-amino]-2-oxo-1-azetidinyl]oxy]acetic acid-1,1 -dimethylethyl- ;ester;A) O-(t-butyloxycarbonylmethyl)-α-N-(benzyloxycarbonyl)-L-serine- hydroxamate ;A solution of dicyclohexylcarbodiimide (57.5 g, 0.28 mol); in dry tetrahydrofuran (60 ml ) was added dropwise to a solution of N-α-(benzyloxycarbonyl-L-serine (66.9 g, 0.28 mol), 1-hydroxybenzotriazole hydrate (42.0 g, 0.28 mol) and t-butylaminooxyacetate (41 .2 g, 0.28 mol) in dry tetrahydrofuran (1.4 liters); at 0-5°C. The mixture was stirred overnight at room temperature. The precipitate (dicyclohexylurea) was removed by filtration and the filtrate evaporated under vacuum. The residue was dissolved in ethyl acetate, washed with 5% NaHCO^ and with water. Drying over MgSO^, followed by filtration and evaporation, gave a crude oil which solidified on treatment with an ice-cold mixture of ether and petroleum ether (1:2 ); yield: 83.6 g, ; mp 64-68° C. ; B) (S)-[[3-[(benzyloxycarbonyl)amino-2-oxo-1-a zetidinyl]-oxy]acetic acid-1,1-dimethylethyl- ester;Method I;Triphenylphosphine (26.2 g, 0.1 mol) was added to a solution of 0-(t-butoxycarbonylmethyl)-α-N-(benzyloxycarbonyl) -L-serine hydroxamate (36.8 g, 0.1 mol) in 500 ml of dry acetonitrile. A solution of triethylamine (20.9 mL, 0.15 mol) and carbon tetrachloride (9.7 mL, 0.1 mol) in 50 mL of dry acetonitrile was added dropwise at room temperature, after which the mixture was stirred overnight and evaporated under vacuum. The residue was dissolved in chloroform, washed with aqueous buffer solution pH 4 (citrate/HCl), dried over MgSO 4 and filtered. The solvent was then removed under reduced pressure and the residue chromatographed on silica gel with ether/ethyl acetate (2:1). Recrystallization of the product from ether/petroleum ether gave colorless crystals; yield 20.6 g, m.p. 87-88°C. ;Method II;Dry pyridine (4.75 g, 60 mmol) was added to a solution of O-(t-butyloxycarbonylmethyl)-α-N-(benzyloxycarbonyl)-L-serine hydroxamate (11.05 g, 30 mmol) in 150 ml dry dichloromethane. A solution of methanesulfonyl chloride (6.8 g, 60 mmol) in 6 mL of dichloromethane was added dropwise to the mixture at 0°C. The mixture was stirred overnight at room temperature, poured into ice-cold water and extracted repeatedly with dichloromethane. The combined organic layers were washed twice with dilute HCl, with water, 5% NaHCO 3 , again with water and then dried over MgSO 4 . After filtration and concentration under vacuum, an oil was obtained which turned into solid form on stirring with ether. 9.4g; m.p. 92-94°C. ;This product together with the product from a new run (total 11.2 g, 26 mmol) in 50 ml of dry acetone, was added dropwise under reflux conditions to a suspension of anhydrous potassium carbonate (21.1 g, 0.15 mol) in 100 ml of dry acetone. The mixture was vigorously stirred and refluxed for 1.5 hours, then cooled to room temperature, filtered and evaporated under vacuum. The residue was dissolved in ether, washed with water and dried over MgSO 4 . Filtration and concentration under vacuum afforded the crude title compound which was recrystallized from ether/petroleum ether; yield 7.41 g, m.p. 82-85°C. ;C) [3S(Z)]-[[3-[[(2-amino-4-thiazolyl)(methoxyimino)acetyl]-amino]-2-oxo-1-azetidinyl]oxy]acetic acid-1,1- Dimethyl ethyl ester; (S)-[[3-[(benzyloxycarbonyl)amino]-2-oxo-1-azetidinyl]-oxy]acetic acid 1,1-dimethylethyl ester (1.4 g, 4.0 mmol) was dissolved in 25 ml of dry dimethylformamide and hydrogenated with 1 g of 10% palladium-on-carbon as catalyst. After 20 minutes, the catalyst was filtered off and a mixture of (Z)-2-amino-α-(methoxyimino)-4-thiazoleacetic acid (4.4 mmol), 1-hydroxybenzotriazole hydrate (0.15 g, 1.0 mmol) , dicyclohexylcarbodiimide (0.81 g, 4.4 mmol) and 30 mL of dry dimethylformamide added. The mixture was stirred overnight at room temperature. The precipitated dicyclohexylurea was filtered off and the solvent removed under vacuum. The residue was dissolved in ethyl acetate, washed with 5% NaHCO 3 and dried over MgSO 4 . Filtration and evaporation under vacuum afforded the title compound which solidified upon stirring with ether/petroleum ether; m.p. 120°C (decomp.). Example 2-5 By following the procedure in Example IC, but with the compound indicated in column I instead of (Z)-2-amino-α-(methoxyimino)-4-thiazoleacetic acid, the compounds indicated in column II were obtained. ; Example 6 ;(3S-trans)-[[3-[(benzyloxycarbonyl)amino]-4-methyl-2-oxo-1-azetidinyl]oxy]acetic acid-1,1-dimethyl ester;A) O-(t-butyloxycarbonylmethyl) )-α-N-(benzyloxycarbonyl)-L-threonine hydroxamate; By following the procedure of Example 1A, but with N-α-(benzyloxycarbonyl)-L-threonine instead of N-α-(benzyloxycarbonyl)-L-serine, the title compound was obtained in form of an oil which solidified on stirring with dichloromethane/petroleum ether overnight; m.p. 57-58°C. ;B) (3S-trans)-t[3-[(benzyloxycarbonyl)amino]-4-methyl-2-oxo-1-azetidinyl]oxy]acetic acid-1,1-dimethylethyl ester ;By following the procedure from example 1B ( method I), but with 0-(t-butyloxycarbonylmethyl)-α-N-(benzyloxycarbonyl)-L-threonine hydroxamate instead of 0-(t-butyloxycarbonylmethyl)-α-N-(benzyloxycarbonyl)-L-serine hydroxamate, the title compound was achieved. After chromatography and several weeks of refrigeration, the oily product crystallized; mp. about 30°C. ;Example 7 ;(S)-[t 3-[(benzyloxycarbonyl)amino]-2-oxo-1-azetidinyl]-oxy] acetic acid diphenylmethyl ester ;A) O-(diphenylmethoxycarbonylmethyl)-a-N-(benzyloxycarbonylmethyl)- L-serine hydroxamate; By following the procedure of Example 1A, but with diphenylmethylaminooxyacetate instead of t-butylaminooxyacetate, the title compound was obtained as a crude oil. ;B) (S)-[[3-[(benzyloxycarbonyl)amino]-2-oxo-1-azetidinyl]-oxy] acetic acid diphenylmethyl ester ;By following the procedure from example 1B (method II), but with 0-( diphenylmethoxycarbonylmethyl)-α-N-(benzyloxycarbonylmethyl)-L-serine hydroxamate instead of β-(t-butyloxycarbonylmethyl)-α-N-(benzyloxycarbonyl)-L-serine hydroxamate, the title compound was obtained as an oil. ;Example 8 ;(3S-trans-2-[[3-[(benzyloxycarbonyl)amino]-4-methyl-2-oxo-1-azetidinyl]oxy]- 2- methylpropanoic acid- diphenylmethyl ester A) 0-[1-methyl -1-(diphenylmethoxycarbonyl)ethyl]-α-N-(benzyloxycarbonyl)-L-threonine hydroxamate t; By following the procedure from example 1A but with N-α-(benzyloxycarbonyl)-L-threonine and diphenylmethylaminooxyisobutyrate instead of N-α-(benzyloxycarbonyl) -L-serine and t-butylamino-oxyacetate, the title compound was obtained. It was dissolved in dry acetonitrile, dried over molecular sieves (3Å) and evaporated under vacuum to a crude oil. ;B) (3S-trans)-2-[[3-[(benzyloxycarbonyl)amino]-4-methyl-2-oxo-1-azetidinyl]oxy]-2-methylpropanoic acid diphenylmethyl ester ;By following the procedure in example 1B (method I) , but with 0-[1-methyl-1-(diphenylmethoxycarbonyl)ethyl]-α-N-(benzyloxycarbonyl)-L-threonine hydroxamate instead of 0-(t-butyl-oxycarbonylmethyl)-α-N-(benzyloxycarbonyl) )-L-serine hydroxamate, the title compound was obtained. Recrystallization of the chromatographically purified product from ether/petroleum ether led to colorless crystals, m.p. 115°C (decomp.). ;Example 9 ;(3S-trans-[ [ 3-[(t-butyloxycarbonyl)amino]-4-methyl-2-oxo-1-azetidinyl] oxy] acetic acid diphenylmethyl ester ;A) O-[1-methyl-1 -(diphenylmethoxycarbonyl)ethyl]-α-N-(t-butyloxycarbonyl)-L-threonine hydroxamate; By following the procedure from Example 1A, but with N-α-(t-butyloxycarbonyl)-L-threonine and diphenylmethylaminooxyacetate instead of N-α-( benzyloxycarbonyl)-L-serine and t-butylaminooxyacetate, the title compound was obtained, m.p. 87-92°C; B) (3S-trans)-[[3-[(t-butyloxycarbonyl)amino]-4-methyl-2-oxo-1-azetidinyl] oxy] acetic acid diphenyl methyl ester ; By following the procedure from Example 1B (Method I), but with 0-[1-methyl-1-(diphenylmethoxycarbonyl)ethyl]-α-N-(t-butyloxycarbonyl)-L-threonine hydroxamate instead of 0-(t-butyloxycarbonylmethyl)-α-N- (benzyloxycarbonyl)-L-serine hydroxamate, the title compound was obtained as a colorless oil which crystallized on stirring with petroleum ether; ;m.p. 73-74° C. ;Example 10 ;(3S-trans)-[[3-[(benzyloxycarbonyl )amino]-4-methyl-2-oxo-1-azetidinyl]oxy]acetic acid methyl ester u ;A) O-(methoxycarbonylmethyl)-a-N-(benzyloxycarbonyl)-L-threonine hydroxamate ;By following the procedure from example 1A , but with N-α-(benzyloxycarbonyl)-L-threonine and methylaminooxyacetate instead of N-α-(benzyloxycarbonyl)-L-serine and t-butylaminooxyacetate, the title compound was obtained, m.p. 99-100°C. ;B) (3S-trans)-[[3-[(benzyloxycarbonyl)amino]-4-methyl-2-oxo-1-azetidinyl]oxy] acetic acid methyl ester ;By following the procedure from example 1B (method I), but with 0-(methoxycarbonylmethyl)-α-N-(benzyloxycarbonyl)-L-threonine hydroxamate instead of 0-(t-butyloxycarbonylmethyl)-α-N-(benzyloxycarbonyl)-L-serine hydroxamate, the title compound was obtained as a colorless oil. ;Example 11 ;(S)-[[3-t(phenylacetyl)amino]-2-oxo-1-azetidinyl]oxy]-acetic acid dipheny Ime ethyl ester ;A) O-(diphenylmethoxycarbonylmethyl)-a-N-( phenylacetyl)-L-serine hydroxamate; By following the procedure of Example 1A, but with N-α-(phenylacetyl)-L-serine and diphenylmethylaminooxyacetate instead of N-α-(benzyloxycarbonyl)-L-serine and t-butylaminooxyacetate, the title compound was obtained (chloroform/acetone was used as eluent in the chromatography), m.p. 89-91°C. ;B) (S)-[t 3-[(phenylacetyl)amino]-2-oxo-1-azetidinyl]oxy]-acetic acid diphenylmethyl ester ;By following the procedure from example 1B (method I), but with 0-( diphenylmethoxycarbonylmethyl)-α-N-(phenylacetyl)-L-serine hydroxamate instead of O-(t-butyloxycarbonylmethyl)-α-N-(benzyloxycarbonyl)-L-serine hydroxamate, the title compound was obtained as a colorless oil. ;Example 12 ;(S)-2-[[3-[(phenylacetyl)amino]-2-oxo-1-azetidinyl]oxy]-2-methylpropanoic acid diphenylmethyl ester ;A) 0-[1-methyl-1-( diphenylmethoxycarbonyl)ethyl]-a-N-(phenyl-acetyl)-L-serine hydroxamate; By following the procedure from example 1A, but with N-a-(phenylacetyl)-L-serine and diphenylmethylaminooxyisobutyrate instead of N-a-(benzyloxycarbonyl)-L -serine and t-butylaminooxyacetate, the title compound was obtained (chloroform/acetone was used as eluent in the chromatography) in the form of an oil which was dissolved in dry acetonitrile, dried over molecular sieves (3Å) and evaporated under vacuum. ;B) (S)-2-[[3-[(phenylacetyl)amino]-2-oxo-1-azetidinyl]-oxy]- 2- methylpropanoic acid diphenylmethyl ester ;By following the procedure from example 1B (method I), but with 0-[1-methyl-1-(diphenylmethoxycarbonyl)ethyl]-α-N-(phenyl-acetyl)-L-serine hydroxamate instead of 0-(t-butyloxy-carbonylmethyl)-α-N-(benzyloxycarbonyl)-L -serine hydroxamate, the title compound was obtained, m.p. 63-73°C decomp. ;Example 13 ;(3S-trans)-[[3-[(phenylacetyl)amino]-4-methyl-2-oxo-1-azetidinyl]oxy] acetic acid diphenylmethyl ester ;A) O-(diphenylmethoxycarbonylmethyl)-a-N-( phenylacetyl)-L-threonine hydroxamate; By following the procedure of Example 1A, but with N-α-(phenylacetyl)-L-threonine and diphenylmethylaminooxyacetate instead of N-α-(benzyloxycarbonyl)-L-serine and t-butylaminooxyacetate, the title compound was obtained , m.p. 119-122°C. ;B) (3S-trans)- f[3[(phenylacetyl)amino]-4-methyl-2-oxo-1 - azetidinyl]oxy] acetic acid diphenylmethyl ester ;By following the procedure from example 1B (method I), but with O-(diphenylmethoxycarbonylmethyl)-α-N-(phenylacetyl)-L-threonine hydroxamate in place of O-(t-butyloxycarbonylmethyl)-α-N-(benzyloxycarbonyl)-L-serine hydroxamate, the title compound was obtained as an oil. ;Example 14 ;(3S-trans)-2-[[3-[(phenylacetyl)amino]-4-methyl-2-oxo-1-azetidinyl]oxy]- 2- methylpropanoic acid- diphenylmethyl ester A) 0-[ 1- methyl-1-(diphenylmethoxycarbonyl)ethyl]-a-N-(phenyl-acetyl)-L-threonine hydroxamate; By following the procedure from example 1A, but with N-a-(phenylacetyl)-L-threonine and diphenylmethylaminooxyisobutyrate instead of N-a - (benzyloxycarbonyl)-L-serine and t-butylaminooxyacetate, the title compound was obtained, mp 88°C. ;B) (3S-trans)-2-[[3-[ (phenylacetyl)amino]-4-methyl-2-oxo-1-azetidinyl]oxy]- 2- methylpropanoic acid diphenylmethyl ester ;By following the procedure from example 1B (method I), but with 0-[ 1-methyl-1-diphenylmethoxycarbonyl)ethyl]-α-N-(phenyl-acetyl)-L-threonine hydroxamate instead of 0-(t-butyloxy-carbonylmethyl)-α-N- (benzyloxycarbonyl)-L-serine hydroxamate, the title compound was obtained, m.p. 78°C. decomp. ;Example 15 ;[3S(Z)]-[[3-[[(2-amino-4-thiazolyl)(methoxyimino)-acetyl]-amino]-2-oxo-1-azetidinyl]oxy]acetic acid potassium salt; N-methyl-N-trimethylsilyltrifluoroacetamide (0.20 g, 1.0 mmol) ; (hereafter MSTFA) was added to a suspension of [3S(Z)]-[[3-[[(2-amino-4-thiazolyl )(methoxyimino)acetyl]amino]-2-oxo-1-azetidinyl]oxy]acetic acid-1,1-dimethylethyl ester (0.20 g, ;0.5 mmol; see Example 1) in 5 ml of dry acetonitrile at 0° C. Stirring was continued for 30 min at 0°C and iodotrimethylsilane (0.10 g, 0.5 mmol) was added. After stirring for 30 minutes at room temperature, the mixture was evaporated under vacuum. The residue was taken up in 5 ml of absolute ether and 0.5 ml of methanol was added. The precipitate was filtered off 30 minutes later, suspended in 5 ml of ice-cold water, after which the pH was adjusted to 6.5 with 1N potassium hydroxide. Chromatography (reversed phase) of the suspension on PH-20 resin with water as eluent, and freeze-drying of the appropriate fractions, led to 120 mg of the title compound; m.p. >170°C decomp. ;Example 16 ;[3S(R)]-[[3-[[[[(4-ethyl-2,3-dioxo-1-piperazinyl)carbonyl]-amino]phenylacetyl]amino]-2-oxo-1- azetidinyl]oxy]acetic acid sodium salt ;Removal of the ester group from [3S(R)]-[13-[[[[(4-ethy1-2,3-dioxo-1-piperazinyl)carbonyl]amino]phenylacetyl]amino]- 2-oxo-1-azetidinyl]oxy]acetic acid-1,1-dimethylethyl ester (see Example 3) was obtained using MSTFA and iodotrimethylsilane as described in Example 15. After decomposition of the crude silylated product with methanol in ether, 0 .5 ml of propylene oxide and ice-cold water added, after which the pH was adjusted to 6.5 with 5% NaHCO 3 . The organic layer was separated and the aqueous phase freeze-dried, whereby after chromatography on HP-20 with 3:4 water/acetone as eluent, a yield of 230 mg was obtained; mp. >160°C decomp. ;Example 17 ;[3S-[3a(R),40]]-[[3-[[[[(4-ethyl-2,3-dioxo-1-piperazinyl)-carbonyl]amino]phenylacetyl]amino]- 4-methyl-2-oxo-1-azetidinyl]-oxy] acetic acid- 1, 1- dimethylethyl ester ;(3S-trans)-[[3-[(benzyloxycarbonyl)amino]-4-methyl-2-oxo-1- Azetidinyl]oxy]acetic acid 1,1-dimethylethyl ester (1.53 g, 4.2 mmol) (see Example 6) was dissolved in 20 ml of dry dimethylformamide. After adding 1.4 g of palladium-on-carbon (10%) catalyst, a stream of nitrogen was bubbled through the solution for about 1 hour. After filtration, a reaction mixture (30 minutes, 0°C) consisting of (R)-α-[[(4-ethyl-2,3-dioxo-1-piperazinyl)carbonyl]-amino]benzeneacetic acid (1.34 g, 4.2 mmol), 1-hydroxy-benzo-triazole hydrate (0.70 g) and dicyclohexylcarbodiimide (0.92 g, 4.4 mmol) in 30 ml dry dimethylformamide added and the mixture stirred overnight at room temperature. The precipitated urea was filtered off, the solvent removed under vacuum and the residue chromatographed on silica gel with ethyl acetate as eluent. The oily product crystallized out on treatment with petroleum ether. Yield: 0.25 g, m.p. 103-110°C decomp. ;Example 18 ;[3S-[3a(Z) ,43]]-[[3-[[(2-amino-4-thiazolyl) (methoxyimino)acetyl] - amino]- 4- methyl- 2- oxo- 1 - azetidinyl] oxy] acetic acid sodium salt; MSTFA (0.43 mL, 2.2 mmol) was added to a solution of (3S-trans)-[[3-[(benzyloxycarbonyl)amino]-4-methyl-2- oxo-1-azetidinyl]oxy]acetic acid 1,1-dimethylethyl ester (0.73 g, ;2.0 mmol) (see example 6) in 20 ml of dry acetonitrile at 0°C. Iodotrimethylsilane (0.56 mL, 4.4 mmol) was added 30 minutes later at 0°C, after which stirring was continued for 30 minutes at room temperature. After evaporation under vacuum, the residue was dissolved in 15 ml of dry tetrahydrofuran. (Z)-2-amino-α-(methoxyimino)-4-thiazoleacetic acid-1-hydroxybenzotriazole ester (0.64 g, 2.0 mmol) was added and the mixture stirred overnight at room temperature. The solvent was removed under vacuum. After addition of ether and ice-cold water, the pH was adjusted to 6.5 with NaHCO^ The organic layer was separated and the aqueous phase freeze-dried. Chromatography on HP-20 with 8:2 water/acetone as eluent gave the title compound (260 mg). ;Example 19 ;[3S-[3a(Z),4 3]]-[[3-[[ (2-amino-4-thiazolyl)-[(1-carboxy-1-methylethoxy)imino]acetyl]amino] -4-methyl-2-oxo-1-azetidinyl]-oxy] acetic acid disodium salt; By following the procedure in example 18, but with (Z)-2-amino-α-[[2-(diphenylmethoxy)-1, 1-Dimethyl-2-oxoethoxy]imino]-4-thiazoleacetic acid-1-hydroxybenzotriazole ester instead of (Z)-2-amino-α-(methoxyimino)-4-thiazoleacetic acid-1-hydroxybenzotriazole ester was obtained [3S -[3a(Z),43]]-[[3-[[(2-amino-4-thiazolyl)]]2-(diphenylmethoxy)-1,1-dimethyl-2-oxoethoxy]imino]-acetyl]amino ]-4-methyl-2-oxo-1-azetidinyl]oxy]acetic acid sodium salt. The product was lyophilized and suspended in a solution of trifluoroacetic acid (10 mL) and anisole (1 mL) at -10°C. The trifluoroacetic acid was distilled off 10 minutes later at 0°C, whereupon ether and ice-cold water were added and the pH adjusted to 6.5 with NaHCO 3 . After lyophilization of the aqueous phase, the crude product was chromatographed on HP-20 with water as eluent; mp. 200°C decomp. ;Examples 20-22;By following the procedure in Example 1C, but with (3S-trans)-[[3-[(benzyloxycarbonyl)amino]-4-methyl-2-oxo-1-azetidinyl]oxy]acetic acid methyl ester (see Example 10) instead of (S)-[[3-[(benzyloxycarbonyl)amino]-2-oxo-1-azetidinyl]-oxy]-acetic acid 1,1-dimethylethyl ester and the acid indicated in column I instead for (Z)-2-amino-α-(methoxyimino)-4-thiazole-acetic acid, the compound indicated in column II was obtained. 20. (Z)-2-amino-a- [3S-[3a(Z),43]]-[[3-[[(2-(methoxyimino)-4-amino-4-thiazolyl)(methoxythiazoleacetic acid imino)]acetyl]amino]-4-methyl-2-oxo-1-azetidinyl]-oxy]acetic acid methyl ester; mp. 99°C decomp. ; 21. (Z)-2-amino-a- [3S-[3a(Z),43]]-t[3-[[(2-[[2-(diphenyl-amino-4-thiazolyl)[[2-( diphenyl-methoxy)-1,1- methoxy)-1,1-dimethyl-2-oxo-dimethyl-2-oxo-ethoxy]imino]acetyl]amino]-ethoxy]imino]-4- 4-methyl-2- oxo-1-azetidinyl]-thiazoleacetic acid oxy]acetic acid methyl ester; mp. 88-90°C decomp. ; 22. (R)-a-[[ (4-ethyl-2,3- [3S-[3a(R) ,43]3-t[3-[[[[(4-dioxo-1-piperazinyl)- ethyl- 2,3-dioxo-1-piperazinyl)carbonyl]amino]carbonyl]amino]phenylacetyl]benzeneacetic acid amino]-4-methyl-2-oxo-1-azetidinyl]oxy]acetic acid methyl ester; m.p. 100°C decomp. ;Example 23;[3S-[3a (Z) , 43]]-[[3-[[(2-amino-4-thiazolyl) [(1-carboxy-1-methylethoxy)imino]acetyl]amino]-4 -methyl-2-oxo-1-azetidinyl]-oxy] acetic acid methyl ester sodium salt; Using trifluoroacetic acid, anisole and sodium bicarbonate (as described in Example 19), the title compound was prepared from [3S-[3a(Z),43 ]]-[[3-[[(2-amino-4-thiazolyl)-[[2-(diphenylmethoxy)-1,1-dimethyl-2-oxoethoxy]imino]acetyl]-amino]-4-methyl-2 -oxo-1-azetidinyl]oxy]acetic acid methyl ester; m.p. about 19 2°C decomp. ;Example 24 ;[3S-[3a(R),43]]-[[3-[[[[[(4-methoxyphenyl)methoxy]carbonyl]-amino]phenylacetyl]amino]-4-methyl-2-oxo -1-azetidinyl]oxy]-acetic acid ;(3S-trans)-[[3-[(t-butyloxycarbonyl)amino]-4-methyl-2-oxo-1-azetidinyl]oxy]acetic acid diphenylmethyl ester (4,4 g, ; 10.0 mmol) was dissolved in a solution of 33 ml of trifluoroacetic acid and anisole (3.3 ml; 30.0 mmol) at -10°C. The mixture was evaporated under vacuum 10 minutes later, after which the residue was stirred with ether, filtered off and dried over ^ 2^ 5 to rare crystals of (3S)-[[3-amino-4-methyl-2-oxo-1-azetidinyl] -oxy]acetic acid trifluoroacetate salt (2.87 g yield). The salt (2.87 g, 10.0 mmol) was suspended in dry acetonitrile, MSTFA (5.57 mL, 30.0 mmol) was added and stirring continued for 30 min. After evaporation under vacuum, the residue was dissolved in dry tetrahydrofuran and then added to a mixture of [[[ (4-methoxyphenyl)methoxy]carbonyl]amino]benzeneacetic acid-1-hydroxy-benzotriazole ester (4.3 g, 10.0 mmol) in 25 ml of dry tetrahydrofuran at 0°C, stirred overnight at room temperature and evaporated under vacuum. After addition of ether, the crude silylated product was decomposed with 1 mL of methanol. The solvents were then removed under vacuum and the residue stirred with ether/petroleum ether, whereby colorless crystals of the title compound were obtained. ;Example 25 ;(S)-[[2-oxo-3-[(phenylacetyl)amino]-1-azetidinyl]oxy]-acetic acid sodium salt ;(S)-[[3-[(phenylacetyl)amino]-2 -oxo-1-azetidinyl]-oxy]acetic acid diphenylmethyl ester (1.78 g, 4.0 mmol) (see Example 11) was dissolved in 30 mL of absolute methanol and hydrogenated with 1.2 g of 10% palladium-on-carbon as a catalyst. After 10 minutes, the catalyst was filtered off and the filtrate evaporated under vacuum. The residue was dissolved in a mixture of ether and ice-cold water and the pH adjusted to 6.5 with NaHCO 3 . Chromatography (reversed phase) of the freeze-dried aqueous phase on HP-20 with water/acetone as eluent, followed by freeze-drying of the relevant fractions, gave 255 mg of the title compound, m.p. 56-70°C decomp. ;Example 26 ;(S)-2-[[2-oxo-3-[(phenylacetyl)amino]-1-azetidinyl]oxy]-2-methylpropanoic acid sodium salt ;By following the procedure in example 25, but with 4, 0 mmol (S)-2-[[3-[(phenylacetyl)amino]-2-oxo-1-azetidinyl]oxy]-2-' methylpropanoic acid diphenyl methyl ester (see Example 12) instead of 4.0 mmol (S )-[[3-[(phenylacetyl)amino]-2-oxo-1-azetidinyl]-oxy]acetic acid diphenyl methyl ester, 630 mg of the title compound were obtained, m.p. 88°C. ;Example 27 ;(3S-trans)-[[4-methyl-2-oxo-3-[(phenylacetyl)amino]-1-azetidinyl] oxy] acetic acid sodium salt ;By following the procedure in example 25, but with ( 3S-trans)-[[3-[(phenylacetyl)amino]-4-methyl-2-oxo-1-azetidinyl]-oxy]acetic acid diphenylmethyl ester (see Example 13) instead of (S)-[[3- [(phenylacetyl)amino]-2-oxo-1-azetidinyl]oxy]acetic acid diphenyl methyl ester, the title compound was obtained, m.p. 77-130°C decomp. ;Example 28 ;(3S-trans)-2-[[4-methyl-2-oxo-3-[(phenylacetyl)amino]-1-azetidinyl]oxy]-2-methylpropanoic acid sodium salt ;By following the procedure in example 15, but with (3S-trans)-2-[[3-[(phenylacetyl)amino]-4-methyl-2-oxo-1-azetidinyl]oxy]-2-methylpropanoic acid diphenylmethyl ester (see example 14), in instead of (S)-[[3-[(phenylacetyl)amino]-2-oxo-1-azetidinyl]oxy]acetic acid diphenylmethyl ester, the title compound was obtained, m.p. 135-14 5°C decomp. ;Example 29 ;(3S-trans)-2-[[3-[(benzyloxycarbonyl)amino]-4-methyl-2-oxo-1- azetidinyl]oxy]- 2- methylpropanoic acid ;(3S-trans)-2- [[3-[(benzyloxycarbonyl)amino]-4-methyl-2-oxo-1-azetidinyl]oxy]-2-methylpropanoic acid diphenyl methyl ester (1.51 g, 3.0 mmol) (see Example 8), was stirred with a solution of 1 ml of anisole in 10 ml of trifluoroacetic acid at -10°C for 10 minutes. The mixture was evaporated under vacuum and the residue dissolved in ether. After adding petroleum ether, the resulting precipitate was collected; yield 0.85 g, m.p. 125-126°C decomp. ;Example 30 ;[3S-[3a(Z),43]]-2-[[3-[[(2-amino-4-thiazolyl)(methoxyimino)-acetyl]amino]-4-methyl-2-oxo -1-azetidinyl]oxy]-2-methylpropanoic acid sodium salt; By following the procedure in example 18, but with (3S-trans)-2-[[3-[(benzyloxycarbonyl)amino]-4-methyl-2-oxo -1-azetidinyl]oxy]-2-methylpropanoic acid (see Example 29) instead of (3S-trans)-[[3-[(benzyloxycarbonyl)amino]-4-methyl-2-oxo-1-azetidinyl]oxy] acetic acid 1,1-dimethylethyl ester, the title compound was obtained, m.p. >190°C decomp. ;Example 31 ;(3S-trans)-2-[[3-[(benzyloxycarbonyl)amino]-4-methyl-2-oxo-1-azetidinyl]oxy]-2-methylpropanoic acid methyl ester, ;To a stirred suspension of (3S-trans)-2-[[3-[(benzyloxycarbonyl )amino]-4-methyl-2-oxo-1-azetidinyl]oxy]-2-methylpropanoic acid (1.68 g, 5.0 mmol) (see example 29) in 10 ml of dry dichloromethane, was added 4-dimethylaminopyridine (30 mg), dry methanol (0.81 ml, 210 mmol) and dicyclohexylcarbodiimide (1.13 g, 5.5 mmol) at 0°C. The reaction mixture was stirred for 3 hours at room temperature. The precipitate (dicyclohexylurea) was removed by filtration and the filtrate evaporated under vacuum. The residue was taken up in ether, filtered, washed with aqueous buffer solution pH 4 (citrate/HCl), NaHCG^ solution, dried over MgSO^ and filtered. Evaporation under vacuum gave the title compound. ;Example 32 ;[3S-[3a(Z) ,43]]-2-[[3-[[(2-amino-4-thiazolyl) [[ (1-carboxy-1-methyl)ethoxy]imino]acetyl ]amino]-4-methyl-2-oxo-1-azetidinyl]-oxy]- 2- methylpropanoic acid methyl ester sodium salt; By following the procedure in examples 1C and 23, but with (3S-trans)-2-[[ 3-[(benzyloxycarbonyl)amino]-4-methyl-2-oxo-1-azetidinyl]oxy]-2-methylpropanoic acid methyl ester (see Example 31), the title compound was obtained, m.p. >150°C decomp. ;Example 33 ;(3S-trans)-[[3-[(t-butyloxycarbonyl)amino]-4-methyl-2-oxo-1- azetidinyl]oxy] acetic acid diphenylmethyl ester ;A) (3S-trans)-3 -(t-butyloxycarbonylamino)-1-hydroxy-4-methyl-2-azetidinone; (3S-trans)-3-(t-butyloxycarbonylamino)-1-benzyloxy-4-methyl-2-azetidinone (10.2 g, 33.3 mmol) was dissolved in dry methanol and hydrogenated with 1.66 g palladium-on-carbon (10%) as catalyst. After 45 minutes, the catalyst was filtered off and the filtrate was evaporated to dryness under reduced pressure. ;Stirring the residue (6.94 g) with ether/petroleum ether gave the title compound; yield 6.6 0 g, m.p. >144°C decomp. ;B) (3S-trans)-[[3-[(t-butyloxycarbonyl)amino]-4-methyl-2-oxo-1- azetidinyl] oxy] acetic acid diphenylmethyl ester ;Triethylamine (0.61 g, 6.0 mmol) was added dropwise to a solution of (3S-trans)-3-(t-butyloxycarbonylamino)-1-hydroxy-4-methyl-2-azetidinone (1.08 g, 5.0 mmol) and diphenylmethylchloroacetate (1, 43 g, 5.5 mmol) in 10 ml of dry dimethylformamide. The mixture was stirred overnight at room temperature. The precipitate was removed by filtration and the solvent evaporated under vacuum. The residue was taken up in ethyl acetate, filtered, washed with 5% NaHCO 4 solution and water, dried over MgSO 4 , and evaporated under vacuum to a colorless oil; ;yield 2.0 g. When stored in a refrigerator, the title compound crystallized out, m.p. 73-74°C. ;Example 34 ;(3S-trans)-[[3-[(t-butyloxycarbonyl)amino]-4-methyl-2-oxo-1-azetidinyl]oxy]acetic acid-1,1-dimethylethyl ester ;By following the procedure in Example 3 3B, but with t-butylchloroacetate instead of diphenylmethylchloroacetate, the title compound was obtained as an oil which crystallized on refrigeration. ;Example 35 ;(3S-trans)-[(3-amino-4-methyl-2-oxo-1-azetidinyl)oxy]acetic acid- 1, 1-dimethylethyl ester ;(3S-trans)-[[3-[( t-Butyloxycarbonyl)amino]-4-methyl-2-oxo-1-azetidinyl]oxy]acetic acid 1,1-dimethylethyl ester (1.44 g, 4.4 mmol) (see Example 34) was dissolved in a mixture of 8.8 ml of trifluoroacetic acid and 0.88 ml of anisole at -10°C. The solution was evaporated under vacuum 10 minutes later at 0°C and the residue stirred with ether, filtered off and dried over P2^5 colorless crystals of the trifluoroacetate salt of the title compound; yield 0.61 g, m.p. 111-112°C decomp. The salt (1.38 g, 4.0 mmol) was suspended in dry aceto-distilled under vacuum and the residue taken up in ethyl acetate, washed successively with water, NaHCO^ solution and water, and then dried (N.a^SO^) . After removal of the solvent under vacuum, the resulting oil was stirred with petroleum ether and the insoluble oil separated (0.86 g) and purified by chromatography on SiCl2 with a mixture of ethyl acetate/ether (1:3) as eluent, which gave a colorless oil; yield 0.43 g. ; Example 38 ; (3S-cis)-[(3-amino-4-methyl-2-oxo-1-azetidinyl)oxy]acetic acid trifluoroacetate salt ;A) O-(diphenylmethoxycarbonylmethyl)-N-t- butyloxycarbonyl-allo-L-threonine; By following the procedure of Example 1A, but with N-t-butyloxycarbonyl-allo-L-threonine and diphenylmethylaminooxyacetate instead of N-a-(benzyloxycarbonyl)-L-serine and t-butylaminooxyacetate, the title compound was obtained, mp. 140-143°C; B) (3S-cis)-[[3-[(t-butoxycarbonyl)amino]-4-methyl-2-oxo-azetidinyl ] oxy ] acetic acid diphenyl methyl ester ; By following the procedure from Example 1B (Method I), but with O-(diphenylmethoxycarbonylmethyl)-N-t-butyloxycarbonyl-allo-L-threonine instead of O-(t-butyloxycarbonylmethyl)-α-N-(benzyloxycarbonyl)-L-serih-hydroxamate, was the title compound obtained. After chromatography on silica gel with ethyl acetate/ether as eluent, the oily product turned into solid form on stirring with petroleum ether; m.p. 105-108°C. ;C) (3S-cis)-[(3-amino-4-methyl-2-oxo-1-azetidinyl)oxy]-acetic acid trifluoroacetate salt ;(3S-cis)-[[3-[(t-butoxycarbonyl) amino]-4-methyl-2-oxo-1-azetidinyl]oxy]acetic acid diphenylmethyl ester (1.5 g, 3.5 mmol) was dissolved in a mixture of 15 ml of trifluoroacetic acid and 1.5 ml of anisole at -10° C. After standing at 0°C for 10 minutes, 30 ml of ether was added. The precipitate was filtered off, washed with ether and dried under vacuum over P2°5 to a hygroscopic solid; yield 0.53 g. ; Example 39 ; (3S-trans)-[[3-[(t-butyloxycarbonyl)amino]-4-methyl-2-oxo-1-azetidinyl] oxy] acetic acid phenylmethyl ester ;A) N 2-(t-butyloxycarbonyl)-N-(phenylmethoxy)-L-threoninamide N-(t-butyloxycarbonyl)-L-threonine (82.2 g) was dissolved in one liter of ethyl acetate and 40.5 g of dimethyl(phenylmethyl) amine. After stirring for 10 minutes, the mixture was cooled to -10°C and 31.05 g of methyl chloroformate was added dropwise. The mixture was stirred for 30 minutes at -10°C, after which a solution of 0.65 g of (phenylmethoxy)amine in 300 ml of ethyl acetate was added at -10°C. The temperature was then allowed to rise to 5°C over a 90 minute period. The reaction mixture was then evaporated under vacuum and redissolved in one liter of ethyl acetate. The insoluble material was filtered off and, under cooling, washed with water, dilute hydrochloric acid (pH of aqueous phase not below 2.5), sodium bicarbonate and saline. After drying (MgSO 4 ) and removal of the solvent under vacuum, an oil was obtained which crystallized on treatment with petroleum ether to give 79.4 g of the title compound, m.p. 87°C. ;B) N 2-(t-butyloxycarbonyl)-0-(methylsulfonyl)-N-(phenyl-methoxy)-L-threoninamide ;N 2-(t-butyloxycarbonyl)-N-(phenylmethoxy)-L-threoninamide (244 g) was dissolved in 1.2 liters of pyridine and the solution cooled to 0°C. While stirring at 0-5°C, 120 g of methanesulfonyl chloride were added dropwise. After 2.5 hours, the reaction mixture was poured into a mixture of 1500 ml of 2N hydrochloric acid and ice, and the pH of the mixture was adjusted to 4 by adding concentrated HCl. The title compound crystallized out and, after 1 hour, was filtered off and washed with water and petroleum ether. After drying at room temperature, 356.4 g were obtained which contained a good amount of water; m.p. 128-130°C decomp. ;C) (3S-trans)-3-[(t-butyloxycarbonyl)amino]-4-methyl-2-oxo-1-(phenylmethoxy)azetidine ;Potassium carbonate (200 g) was dissolved in 300 ml of water, added 1, 5 liters of 1,2-dichloroethane and the mixture refluxed. A suspension of 178 g of N 2-(t-butyloxycarbonyl)-0-(methyl-;41. (3S-trans)-[[3-[(t-butyloxycarbonyl)amino]-4-methyl-2-oxo-1 -azetidinyl]oxy]acetic acid-2-hydroxyethyl ester 4 2. (3S-trans)-[[3-[(t-butyloxycarbonyl)amino]-4-methyl-2-oxo-1-azetidinyl]oxy]acetic acid-2- methoxyethyl ester 43. (3S-trans)-[[3-[(t-butyloxycarbonyl)amino]-4-methyl-2-oxo-1-azetidinyl]oxy]acetic acid 2-methylpropyl ester 44. (3S-trans)-[ [3-[(t-butyloxycarbonyl)amino]-4-methyl-2-oxo-1-azetidinyl]oxy]acetic acid-1-ethylpropyl ester 45. (3S-trans)-[[3-[(t-butyloxycarbonyl)amino ]-4-methyl-2-oxo-1-azetidinyl]oxy]acetic acid phenyl ester 46. (3S-trans)-[[3-[(t-butyloxycarbonyl)amino]-4-methyl-2-oxo-1- azetidinyl]oxy]acetic acid-2-methylphenyl ester 47. (3S-trans)-[[3-[(t-butyloxycarbonyl)amino]-4-methyl-2-oxo-1-azetidinyl]oxy]acetic acid-5- indanyl ester 48. (3S-trans)-[[3-[(t-butyloxycarbonyl)amino]-4-methyl-2-oxo-1-azetidinyl]oxy]acetic acid-2-indanyl ester 49. (3S-trans)-[ [3-[(t-butyloxycarbonyl)amino]-4-methyl-2-oxo-1-azeti dinyl]oxy]acetic acid-(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester 50. (3S-trans)-[[3-[(t-butyloxycarbonyl)amino]-4-methyl -2-oxo-1-azetidinyl]oxy]acetic acid-(2,2-dimethyl-1-oxopropoxy)-methyl ester ; Example 51 ;(3S-trans)-[(3-amino-4-methyl-2-oxo- 1-Azetidinyl)oxy]acetic acid-phenyl Imetyle ester- trifluoroacetate salt ;(3S-trans)-[[3-[(t-butyloxycarbonyl)amino]-4-methyl-2-oxo-1-azetidinyl] Oxyacetic acid phenylmethyl ester (3.6 g) was dissolved in 5 ml of dichloromethane and the solution cooled to -10°C. Trifluoroacetic acid (25 ml) was added dropwise and the mixture stirred for 20 minutes at -10°C. After evaporation, the residue was treated with ether, whereby 2.5 g of the title compound was obtained. ;Examples 52-62;By following the procedure of Example 51, but with the appropriate ester in place of (3S-trans)-[[3-[(t-butyloxycarbonyl)amino]-4-methyl-2-oxo-1 -azetidinyl]oxy]acetic acid phenylmethyl ester, the compounds indicated below were obtained. 52. (3S-trans)-[(3-amino-4-methyl-2-oxo-1-azetidinyl)oxy]-acetic acid ethyl ester trifluoroacetate salt 53. (3S-trans)-[(3-amino-4- methyl-2-oxo-1-azetidinyl)oxy]-acetic acid-2-hydroxyethyl ester trifluoroacetate salt 54. (3S-trans)-[(3-amino-4-methyl-2-oxo-1-azetidinyl)oxy]-acetic acid -2-methoxyethyl ester trifluoroacetate salt 55. (3S-trans)-[(3-amino-4-methyl-2-oxo-1-azetidinyl)oxy]-acetic acid 2-methylpropyl ester trifluoroacetate salt 56. (3S-trans)- [(3-amino-4-methyl-2-oxo-1-azetidinyl)oxy]-acetic acid-1-ethylpropyl ester trifluoroacetate salt 57. (3S-trans)-[(3-amino-4-methyl-2-oxo- 1-azetidinyl)oxy]-acetic acid phenyl ester trifluoroacetate salt 58. (3S-trans)-[(3-amino-4-methyl-2-oxo-1-azetidinyl)oxy]-acetic acid 2-methylphenyl ester trifluoroacetate salt 59. (3S-trans)-[(3-amino-4-methyl-2-oxo-1-azetidinyl)oxy]-acetic acid-5-indanyl ester trifluoroacetate salt 60. (3S-trans)-[(3-amino-4- methyl-2-oxo-1-azetidinyl)oxy]-acetic acid-2-indanyl ester trifluoroacetate salt 61. (3S-trans)-[(3-amino-4-methyl-2-oxo-1-azetidinyl)oxy]-eddi (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl ester trifluoroacetate salt ~ 62. (3S-trans)-[(3-amino-4-methyl-2-oxo-1-azetidinyl )oxy]-acetic acid-(2,2-dimethyl-1-oxo-ethoxy)methyl ester trifluoroacetate salt Example 63 [3S-[3a(Z) ,4 3] ]-[[3-[ [ (2-amino-4 -thiazolyl) (methoxyimino)acetyl]-amino]-4-methyl-2-oxo-1-azetidinyl]oxy]acetic acid phenylmethyl-ester (Z)-2-amino-a-(methoxyimino)-4-thiazoleacetic acid (1 .32 g) was dissolved in 22 ml of absolute dimethylformamide and 1.1 mol of triethylamine was added, after which the mixture was cooled to -25°C. Diphenyl phosphochloridate (1.36 mL) was added and the temperature maintained at -25°C for 50 minutes. The mixture was then added to a solution prepared from 2.5 g of (3S-trans)-[(3-amino-4-methyl-2-oxo-1-azetidinyl)oxy]acetic acid phenylmethyl ester trifluoroacetate salt and 4.6 ml of triethylamine in 22 ml of dimethylformamide which had also been cooled to -25°C. The reaction mixture was stirred at -25°C for 2.5 hours and with stirring added 70 ml of 0.5 molar monobasic potassium phosphate, diluted with 70 ml of water and extracted with ethyl acetate. By addition of 2N hydrochloric acid, the pH was adjusted to 6. The aqueous phase was extracted again with ethyl acetate and the combined organic phases washed with water, dried with MgSO 4 , filtered and evaporated to 2.3 g of the title compound in the form of a foam which was treated with petroleum ether and filtered. ;Examples 64-66;By following the procedure of Example 63, but with the appropriate ester in place of (3S-trans)-[(3-amino-4-methyl-2-oxo-1-azetidinyl)oxy]acetic acid- phenyl methyl ester trifluoroacetate salt, the compounds indicated below were obtained. 64. [3S-[3a(Z),43]]-[[3-[[(2-amino-4-thiazolyl)(methoxyimino)-acetyl]amino]-4-methyl-2-oxo-1-azetidinyl ]oxy]acetic acid-(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester 65. [3S-[3a(Z),43]]-[[3-[[(2-amino -4-thiazolyl)(methoxyimino)-acetyl]amino]-4-methyl-2-oxo-1-azetidinyl]oxy]acetic acid-(2,2-dimethyl-1-oxo-propoxy)methyl ester 66. [3S-[ 3a(Z),43]]-[[3-[[(2-amino-4-thiazolyl)(methoxyimino)-acetyl]amino]-4-methyl-2-oxo-1-azetidinyl]oxy]acetic acid-[ (1 - methylethyl)carbamoyl]methyl ester ;Example 6 7 ;[3S-[3a(Z) ,43]]-[[3-[[(2-amino-4-thiazolyl) (methoxyimino)-acetyl]amino]- 4-Methyl-2-oxo-1-azetidinyl]oxy]acetic acid phenyl ester ;(3S-trans)-[(3-amino-4-methyl-2-oxo-1-azetidinyl)oxy]-acetic acid phenyl ester trifluoroacetate salt (2.1 g) was suspended in 50 ml of acetonitrile and 2.1 g of N-methyl(trimethylsilyl)trifluoromethylacetamide was added to obtain a solution. After cooling to 0°C, (Z)-2-amino-α-(methoxyimino)-4-thiazoleacetic acid-N-hydroxybenzotriazole ester was added. The mixture was stirred for 3 hours at room temperature, evaporated under vacuum, redissolved in ethyl acetate, washed (cooling) with salt solution which during washing was adjusted to pH 7. The organic phase was dried (MgSO 4 ), evaporated and the residue treated with ether, whereby 2.6 g of the title compound was obtained. ;Examples 68-73;By following the procedure of Example 67, but with the appropriate ester in place of (3S-trans)-[(3-amino-4-methyl-2-oxo-1-azetidinyl)oxy]acetic acid- phenyl ester trifluoroacetate salt, the compounds indicated below were obtained. 68. [3S-[3a(Z),43]]-[[3-[[(2-amino-4-thiazolyl)(methoxyimino)-acetyl]amino]-2-oxo-1-azetidinyl]oxy]acetic acid -ethyl ester 69. [3S-[3a(Z),43]]-[[3-[[(2-amino-4-thiazolyl)(methoxyimino)-acetyl]amino]-2-oxo-1-azetidinyl]oxy ]acetic acid 2-hydroxyethyl ester 70. [3S-[3a(Z),43]]-[[3-[[(2-amino-4-thiazolyl)(methoxyimino)-acetyl]amino]-2-oxo -1-azetidinyl]oxy]acetic acid 2-methoxyethyl ester 71 . [3S-[3a(Z) ,43]]-[[3-[[(2-amino-4-thiazolyl) (methoxyimino)-acetyl]amino]-2-oxo-1-azetidinyl]oxy]acetic acid-2 -methyl-propyl ester 72. [3S-[3a(Z),43]]-[[3-[[(2-amino-4-thiazolyl)(methoxyimino)-acetyl]amino]-2-oxo-1-azetidinyl ]oxy]acetic acid 1-ethylpropyl ester 73. [3S-[3a(Z),43]]-[[3-[[(2-amino-4-thiazolyl)(methoxyimino)-acetyl]amino]-2-oxo -1-azetidinyl]oxy]acetic acid 2-indanyl ester ;Example 74 ;(3S-trans)-[[3-[(t-butyloxycarbonyl)amino]-4-methyl-2-oxo-1-azetidinyl]oxy ] acetic acid potassium salt; (3S-trans)-[[3-[(t-butyloxycarbonyl)amino]-4-methyl-2-oxo-1-azetidinyl]oxy]acetic acid phenylmethyl ester (3.6 g) was dissolved in 100 ml of methanol. After treatment with activated charcoal, 1.8 g of 5% palladium-on-carbon was added and hydrogen introduced through the stirred mixture at room temperature. After 1 hour, the mixture was filtered, after which the filtrate was diluted with water, neutralized with potassium carbonate and lyophilized, whereby the title compound was obtained. ;Example 75 ;(3S-trans)-[[3-[(t-butyloxycarbonyl)amino]-4-methyl-2-oxo-1-azetidinyl]oxy]acetic acid-(2,2-dimethyl-1-oxopropoxy) methyl ester _ ;(3S-trans)-[[3-[(t-butyloxycarbonyl)amino]-4-methyl-2-oxo-1-azetidinyl]oxy]acetic acid potassium salt (0.01 mol) was dissolved in 40 ml dimethylformamide. The solution was cooled to 0°C and 0.7 ml of triethylamine and then 3.1 g of 2,2-dimethylpropionic acid iodomethyl ester were added. After stirring overnight at 0°C, the solvent was removed in vacuo and the oily residue dissolved in 100 mL ethyl acetate, washed 3 times with ice water, dried (MgSO 4 ) and evaporated to give 2.4 g of the title compound. ;Examples 76-78;By following the procedure of Example 75, but with the appropriate compound in place of 2,2-dimethylpropionic acid iodomethyl ester, the compounds indicated below were obtained. 76. (3S-trans)-[[3-[(t-butyloxycarbonyl)amino]-4-methyl-2-oxo-1-azetidinyl]oxy]acetic acid-(5-methyl-2-oxo-1,3- dioxol-4-yl)methyl ester 77. (3S-trans)-[[3-[(t-butyloxycarbonyl)amino]-4-methyl-2-oxo-1-azetidinyl]oxy]acetic acid-[(1-methylethyl)carbamoyl]-methyl ester 78. (3S- trans)-[[3-[(t-butyloxycarbonyl)amino]-4-methyl-2-oxo-1-azetidinyl]oxy]acetic acid-[(2,2-dimethylethyl)carbamoyl]-methyl ester ;Example 79 ;(S )-[[3-[(benzyloxycarbonyl)amino]-2-oxo-1-azetidinyl]oxy]-acetic acid ;(S)-[[3-[(benzyloxycarbonyl)amino]-2-oxo-1-azetidinyl]- Oxyacetic acid diphenyl methyl ester (15.4 g; see Example 7) was mixed with 4 ml of anisole. At 0°C, 40 ml of trifluoroacetic acid was slowly added and the mixture was kept at this temperature for 10 minutes. The reaction mixture was evaporated under vacuum at room temperature, dissolved in ethyl acetate and evaporated again. The oily residue was dissolved in 100 ml of ethyl acetate, ice-cold water was added and the pH of the mixture adjusted to 6.5. The ethyl acetate phase was then extracted once more with dilute sodium bicarbonate solution. ;The combined aqueous phases were cooled (ice), extracted with 100 ml of ethyl acetate and added with 2N hydrochloric acid to pH 2. The aqueous phase was extracted 2 more times with ethyl acetate and the combined ethyl acetate extracts dried (MgSO 4 ) and evaporated, whereby 6 g of the title compound was obtained as a syrupy product. The title compound was dissolved in a mixture of methanol and water and the solution adjusted to pH 6>5 with dilute sodium hydroxide and freeze-dried, whereby the corresponding sodium salt was obtained as an amorphous solid. ;Example 30 ;(S)-[[3-[(benzyloxycarbonyl)amino]-2-oxo-1-azetidinyl]-oxy]acetic acid-(2,2-dimethyl-1-oxopropoxy)methyl ester ;(S)-[ [3-[(benzyloxycarbonyl)amino]-2-oxo-1-azetidinyl]-oxy]acetic acid (3 g; see Example 79) was dissolved in 200 ml of dimethylformamide and the solution cooled to 0°C. 1,8-diazabicyclo-[5.4.0]-undec-7-ene (0.01 mol) and then 2.7 g of 2,2-dimethylpropionic acid iodomethyl ester were added. After 10 minutes, the mixture was diluted with 75 ml of ethyl acetate, cooled (ice water) and washed with ice cold water, ice cold dilute sodium bicarbonate solution and again with ice cold water. After drying (MgSO 4 ), the filtrate was evaporated, after which 4 g of the title compound crystallized on standing; m.p. 73-75°C. ;Example 81 ;(S)-[[3-[(benzyloxycarbonyl)amino]-2-oxo-1-azetidinyl]-oxy] acetic acid-[( 2, 2-dimethylethoxy)carbonyl] methyl ester, ;By following the procedure in example 80, but with chloroacetic acid 1,1-dimethylethyl ester instead of 2,2-dimethylpropionic acid iodomethyl ester, and by allowing the reaction to extend over 6 hours, the title compound was obtained; m.p. 90-92°C. ;Example 82 ;[3S-[3a(Z),43]]-[[3-[[2-[[(triphenylmethyl)amino]-4-thiazolyl]-[methoxyimino]acety1]amino]-2-oxo- 1-azetidinyl]oxy]acetic acid- 1 -ethylpropyl ester ;A) N-[[2-[(triphenylmethyl)amino]-4-thiazolyl][methoxyimino]-acetyl]- L-threonine ;< L-threonine (11 g) was suspended in 140 ml of acetonitrile. After addition of 46 ml of bistrimethylsilylacetamide, the mixture was refluxed for 1 hour. ;(Z)-2-[(triphenylmethyl)amino]-α-(methoxyimino)-4-thiazole-acetic acid (48.4 g) was dissolved in 250 ml of dimethylformamide and 15.9 g of N-hydroxybenzotriazole and 24.1 g dicyclohexylcarbodiimide. The mixture was stirred for 2 hours at room temperature. The crystals (dicyclohexylurea) were filtered off and the filtrate evaporated under vacuum, after which the residue was dissolved in 300 ml of acetonitrile and combined with the solution of silylated L-threonine. The mixture was stirred overnight at room temperature, filtered, evaporated under vacuum, treated with water and the aqueous phase adjusted to pH 7.5 and extracted with ethyl acetate. The aqueous phase was then added with 2N hydrochloric acid to pH 2.5. The title compound precipitated and was filtered off (46.9 g). ;B) N 2-[[ 2-[ (triphenylmethyl) amino]-4-thiazolyl][methoxyimino] - acetyl]- N-[[(diphenylmethoxy) carbonyl] methoxy]- L-threoninamide ;N-[[2 -[(triphenylmethyl)amino]-4-thiazolyl] [methoxyimino]-acetyl]-L-threonine was reacted with [[(diphenylmethoxy)carbonyl]-methoxylamine according to the procedure described in Example 39A, whereby the title compound was obtained as an amorphous solid. C) N -[[2-[(triphenylmethyl)amino]-4-thiazolyl][methoxyimino]-acetyl]-O-(methylsulfonyl)-N-[[(diphenylmethoxy)carbonyl]-methoxy]- L- threoninamide ;N 2-[[2-[(triphenylmethyl)amino]-4-thiazolyl][methoxyimino]acetyl]-N-[[(diphenylmethoxy)carbonyl]methoxy]-L-threoninamide was mesylated according to the procedure described in Example 39B, whereby the title compound was obtained as an amorphous solid. ;D) [3S-[3a(Z),43]]-[[3-[[2-[[(triphenylmethyl)amino]-4-thiazolyl][methoxyimino]acetyl]amino]-2-oxo-1- azetidinyl]-oxy ] acetic acid diphenylm ethyl ester ;N 2-[[2-[(triphenylmethyl)amino]-4-thiazolyl][methoxyimino] acetyl ] -O-(methylsulfonyl)-N-[[(diphenylmethoxy)carbonyl] -methoxy]-L-threoninamide was treated with potassium carbonate according to the procedure described in Example 39C, whereby the title compound was obtained. ;Example 83 ;[3S-[3a(Z),4 3]]-[[3-[[2-[[(triphenylmethyl)amino]-4-thiazolyl]-[methoxyimino]acetyl]amino]-2-oxo -1-azetidinyl]oxy]acetic acid- 1 -ethylpropyl ester; By following the procedure in example 82, but with [[(1-ethylpropoxy)carbonyl]methoxy]amine instead of [[(diphenyl-methoxy)carbonyl]methoxy]amine , the title compound was obtained. ;Example 84;(alternative preparation of the compound of Example 72);[3S-[3ot(Z),43]]-[[3-[[(2-amino-4-thiazolyl)(methoxyimino)-acetyl]amino] -2-oxo-1-azetidinyl]oxy]acetic acid-1-ethylpropyl ester ;[3S-[3a(Z),43]]-[[3-[[2-[[(triphenylmethyl)amino]-4-thiazolyl] [Methoxyimino]acetyl]amino]-2-oxo-1-azetidinyl]-oxy]acetic acid-1-ethylpropyl ester (1.2 g) was dissolved in 12 ml of 97% formic acid at room temperature. After stirring for 4 hours, the mixture was filtered and the filtrate mixed with 35 ml of dichloromethane. Water was then added, after which the organic phase was washed with water and dilute sodium bicarbonate, dried (MgSO 4 ) and evaporated to 0.43 g of the title compound. ;Example 85 ;[3S-[3a(Z),40]]-[[3-[[(2-amino-4-thiazolyl)(methoxyimino)-acetyl]amino]-2-oxo-1-azetidinyl]oxy ]acetic acid-diphenyl-1-methyl ester ;By following the procedure in example 84, but with [3S-[3a(Z),43]]-[[3-[[2-[[(triphenylmethyl)amino]-4-thiazolyl] [Methoxyimino]acetyl]amino]-2-oxo-1-azetidinyl]oxy]acetic acid diphenylmethyl ester instead of [3S-[3a(Z),40]]-[[3-[[2-[(tri- phenylmethyl)amino]-4-thiazolyl][methoxyimino]acetyl]amino]-2-oxo-1-azetidinyl]oxy]acetic acid-1-ethylpropyl ester, the title compound was obtained. ;Example 86;[3S-[3a(Z), 43]]-[[3-[[(2-amino-4-thiazolyl)(methoxyimino)-acetyl]amino]-4-methyl-2-oxo-1 -azetidinyl]oxy]acetic acid-(5-methyl- 2- oxo- 1, 3- dioxol- 4- yl) methyl ester ;[3S-[3a(Z),43]]-[[3-[[(2- amino-4-thiazolyl)(methoxyimino)-acetyl]amino]-4-methyl-2-oxo-1-azetidinyl]oxy]acetic acid sodium salt (0.95 g, see Example 18) was dissolved in 25 ml of dimethylformamide, cooled to 0°C and added 0.38 g of 1,8-diazabicyclo-[5.4.0]undec-7-ene and then 0.83 g of 5-(bromomethyl)-2-oxo-4-phenyl-1,3- dioxol. After stirring for 4 hours, the dimethylformamide was removed in vacuo and the residue dissolved in ethyl acetate, washed with ice-cold water, sodium bicarbonate solution and brine, dried (MgSO 4 ) and evaporated. The residue was dissolved in ethyl acetate. On addition of petroleum ether, the title compound precipitates as an amorphous solid. ;Example 87 ;[3S-[3a (Z) ,4 |3] ]-[ [3-[ [ (2-amino-4-thiazolyl) (methoxyimino)-acetyl]amino]-4-methyl-2-oxo -1-azetidinyl]oxy]acetic acid-(acetyloxy) methyl ester ;To a solution of [3S-[3a(Z),43]]-[[3-[[(2-amino-4-thiazolyl)(methoxyimino)acetyl ]amino]-4-methyl-2-oxo-1-azetidinyl]oxy]acetic acid sodium salt (3.2 g; see Example 18); in 50 ml of dry dimethylformamide, 1.86 g of chloromethyl acetate was added dropwise with stirring, after which stirring was continued for 3 days. The solvent was evaporated under vacuum and the residue taken up in ethyl acetate, washed successively with ice-cold water, ice-cold aqueous sodium bicarbonate and ice-cold saline and then dried over CaSO 4 . After filtration and removal of the solvent under vacuum, the residue was chromatographed on silica gel with ethyl acetate as eluent, whereby 1.08 g of the title compound was obtained, decomp >74°C. ;Example 88 ;[3S-[3a(Z),43]]-[[3-[[(2-amino-4-thiazolyl)(methoxyimino)-acetyl]amino]-4-(azidomethyl)-2-oxo -1-azetidinyl]oxy]-acetic acid potassium salt, ;A) 5-(chloromethyl)-4,5-dihydro-4-oxazolecarboxamide; 114 g of chloroacetaldehyde monohydrate and 84 g of isocyanoacetamide were dissolved in 1000 ml of methanol. The mixture was cooled to 0-3°C and a solution of 38 g of 1,8-diazabicyclo[5.4.0]undec-7-ene in 200 ml of methanol was added with stirring. At this temperature, stirring was continued for 30 minutes and then for 1 hour after removal of the cooling bath. The solvent was removed under vacuum and the residue refluxed 2 times, each time with 1000 ml of ethyl acetate. The combined hot extracts were treated with activated charcoal and, in the hot state, filtered and evaporated, whereby the title compound was obtained as a crystalline residue which, after recrystallization from ethyl acetate, melted at 110-112°C. ;B) 4-chloro-DL-threoninamide hydrochloride ;5-(chloromethyl)-4,5-dihydro-4-oxazolecarboxamide was dissolved in 1500 ml of 2N hydrochloric acid and heated to 50°C for 2 hours. The hydrochloric acid was removed under vacuum and the residue triturated with isopropanol, whereby the title compound was obtained as brownish crystals; yield 133.9 g. ;C) 4-chloro-DL-threonine; 70 g of 4-chloro-DL-threoninamide hydrochloride was dissolved in; 350 ml of water. The solution was passed through a column filled with 1.8 kg of Amberlyst 15. The column was washed with water to remove the hydrochloric acid. The material was then removed from the column and, with stirring, heated to 60°C for 5 hours. After cooling, the resin was placed in the column again and then eluted with a solution of 5% trichloroacetic acid in water. Fractions containing DL-chloro-threonine were collected, evaporated to a small volume and extracted 4 times with 400 ml portions of ether to remove the trichloroacetic acid. The aqueous phase was freeze-dried and the residue dissolved in 200 ml of isopropanol, from which the title compound was crystallized (yield 27 g). A further product fraction of 7 g was obtained by evaporating the mother liquor, treating the oily residue with ether, removing the ether and re-treating the insoluble material with isopropanol. ;D) N-(t-butyloxycarbonyl)-4-chloro-DL-threonine; 22 g of 4-chloro-DL-threonine were suspended in a mixture of 43 ml of water and 71 ml of t-butanol. By adding 2N sodium hydroxide, the pH was adjusted to 7.0 and 34.3 g of di-tert-butyl pyrocarbonate was added to the mixture and, with stirring, kept at pH 7.5 for 3 hours. Work-up of the reaction mixture gave the title compound as a syrupy product. ;E) , N-(t-butyloxycarbonyl)-4-azido-DL-threonine; 16.8 g of N-(t-butyloxycarbonyl)-4-chloro-DL-threonine were dissolved in 170 ml of methanol and 70 ml of water. The pH of the mixture was adjusted to 11 by adding potassium carbonate (9.5 g), after which 13 g of sodium azide was added and the pH was kept at 11 for 24 hours (room temperature). The methanol was removed under vacuum and the aqueous phase extracted with ethyl acetate and adjusted to pH 2.5 by adding phosphoric acid. The aqueous phase was extracted twice more with ethyl acetate and the combined organic phases dried (MgSO 4 ) and evaporated to give 16.5 g of the syrupy title compound. ;F) [[N 2-(t-butyloxycarbonyl)-4-azido-DL-threoninamido]-oxy] acetic acid diphenylmethyl ester ; 16.4 g of N-(t-butyloxycarbonyl)-4-azido-DL-threonine were dissolved in 250 ml of tetrahydrofuran. To the solution was added 16.3 g of (aminooxy)acetic acid diphenyl methyl ester and 40 ml of water, followed by 0.97 g of N-hydroxybenzotriazole and 13.1 g of drcyclohexylcarbodiimide. After stirring overnight, the precipitated dicyclohexylurea was filtered off. The filtrate was evaporated under vacuum and the oily residue dissolved in ethyl acetate, filtered and washed with sodium bicarbonate solution and saline solution. After drying (MgSO 4 ) and evaporation of the solvent under vacuum, 36 g of crude product in the form of an oil was obtained. The product was purified by chromatography on silica gel eluting with a 70:30 mixture of dichloromethane/ethyl acetate. ;G) [[N 2-(t-butyloxycarbonyl)-4-azido-O-(methylsulfonyl)-DL- threoninamido]oxy] acetic acid diphenyl methyl ester ;6.5 g [[N 2-(t-butyloxycarbonyl)-4 -azido-DL-threonine-amido]oxy]acetic acid diphenylmethyl ester was mesylated according to the method described in Example 39B, whereby 6.8 g of the title compound was obtained as an oil. ;H) (trans)-[[4-(azidomethyl)-3-[(t-butyloxycarbonyl)amino]-2- oxo- 1- azetidinyl3oxy] acetic acid diphenyl methyl ester ; 6.8 g [[N 2-(t -butyloxycarbonyl)-4-azido-O-(methyl-sulfonyl)-DL-threoninamido3oxy3-acetic acid diphenylmethyl ester was cyclized according to the method described in Example 39C, whereby 3.8 g of the title compound was obtained as an oil. ;I) (trans)-[[3-(amino-4-(azidomethyl)-2-oxo-1-azetidinyl]-oxy3 acetic acid trifluoroacetate salt ;3.8 g (trans)-[[4-(azidomethyl)- 3-[(t-Butyloxycarbonyl)-amino]-2-oxo-1-azetidinyl]oxy]acetic acid diphenylmethyl ester was dissolved in 3 ml of anisole at room temperature and cooled to -10° C. At this temperature, 30 ml of trifluoroacetic acid was added , ;after which the mixture was kept at -10°C for 30 minutes. Upon addition of 70 ml of ether, the title compound was precipitated (0.6 g). A further product fraction of 0.6 g was obtained by evaporating the filtrate and treating the oily residue with ether. ;J) [3S-[3oc(Z) ,43] ]-[ [3-[ [ (2-amino-4-thiazolyl) (methoxyimino)-acetyl]amino]-4-(azidomethyl) -2-oxo-1-azetidinyl]oxy]acetic acid potassium salt; 0.33 g of (trans)-[[3-amino-4-(azidomethyl)-2-oxo-1-azetidinyl]oxy]acetic acid trifluoroacetate salt was suspended in 20 ml of acetonitrile and 0.6 ml of N-methyl-N-trimethylsilyltrifluoroacetamide added to achieve dissolution after 30 minutes of stirring. The solution was cooled to 0°C and 0.35 g of (Z)-2-amino-α-(methoxyimino)-4-thiazoleacetic acid-N-hydroxy-benzotriazole ester was added. The mixture was stirred at room temperature for 2.5 hours and 1 ml of a solution of potassium ethyl hexanoate was added, after which the mixture was evaporated under vacuum to a small volume. On addition of ether, the title compound is precipitated in the form of 0.55 g of crude product. This was purified by chromatography on HP-20. The title compound was eluted with water/acetone (80:20); yield 95 mg. ;Example 89 ;(trans)-[[3-(t-butyloxycarbonyl)-4-methyl-2-oxo-1-azetidinyl]-oxy] (methylthio)acetic acid methyl ester ;A) Bromo(methylthio)acetic acid methyl ester; 24.0 g of (methylthio)acetic acid methyl ester, 32.8 g of N-bromosuccinimide and 100 mg of 2,2'-azobis-(2-methylpropionitrile) were heated for 1 hour at 60°C in 150 ml of carbon tetrachloride. After cooling and filtration, the solvent was removed under vacuum and the residue distilled, whereby 26.8 g of bromo(methylthio)-acetic acid methyl ester was obtained as a red oil. ;B) (trans)-[[3-(t-butyloxycarbonyl)-4-methyl-2-oxo-1-azetidinyl]oxy](methylthio)acetic acid methyl ester ;2.16 g 3-[(t-butyloxycarbonyl) amino]-1-hydroxy-4-methyl-2-azetidinone and 2.20 g of bromo(methylthio)acetic acid methyl ester were dissolved in 50 ml of dimethylformamide. Over a period of 3 hours, 1.11 g of triethylamine in 30 ml of dimethylformamide was added, and the mixture was stirred for 2 days at room temperature. The solvent was removed under vacuum and the residue suspended in 20 ml of ethyl acetate. After filtering off the ammonium salt, the solution was concentrated and chromatographed on silica gel with ethyl acetate as eluent, whereby 2.0 g of product was obtained in the form of an oil. ;IR (film): 1780, 1745, 1710 cm"<1>. ;NMR (DMSO-dg): δ = 1.38 (s, 9H), 2.22 (s, 3H), 3.76 (s , 3H), 5.63 and 5.66 (2s, 1H), 7.60 (br, d, 1H). ;Example 90 ;[3S-[3a(Z),43]]-t[3-[ [(2-amino-4-thiazolyl)(methoxyimino)-acetyl]amino]-4-methyl-2-oxo-1-azetidinyl]oxy]acetic acid 1-methylethyl ester ;A) (3S-trans)-3-( t-butyloxycarbonylamino)-1-hydroxy-4-methyl-2-azetidinone; 10.5 g of (3S-trans)-3-(t-butyloxycarbonylamino)-1-benzyloxy-4-methyl-2-azetidinone was dissolved in 250 ml methanol and hydrogenated with 1.43 g of palladium-on-carbon (10%) as catalyst. After 45 minutes, the catalyst was filtered off and the filtrate evaporated under vacuum. The crystalline title compound was dried (vacuum desiccator) at room temperature, whereby 7.3 g of the title compound was obtained; mp 161-16 2°C decomp. ;B) (3S-trans)-[[3-[(t-butyloxycarbonyl)amino]-4-methyl-2-oxo-1-azetidinyl]oxy]acetic acid-1-methylethyl ester; 11.3 g of triethylamine was added dropwise in a solution of 19.5 g of (3S-trans)-3-(t-butyloxycarbonylamino)-1-hydroxy-4-methyl-2-azetidinone and 14.8 g of chloroacetic acid 1-methylethyl ester in 400 ml of dry dimethylformamide, after which the mixture was stirred at room temperature for 3 days. Triethylamine hydrochloride was filtered off and the solvent distilled off under vacuum at 35°C. The remaining oil was taken up in ether and the extract placed in a refrigerator for about 2 hours and then filtered, after which the ether was again evaporated under vacuum. The resulting oily title compound (30 g) containing about 2 g of impurities was used in the next step without further purification. ;C) (3S-trans)-[[3-amino-4-methyl-2-oxo-1-azetidinyl]oxy]-acetic acid- 1- methylethyl ester- trifluoroacetate ; 30 g impure (3S-trans)-[[3 -[(t-butyloxycarbonyl)-amino]-4-methyl-2-oxo-1-azetidinyl]oxy]acetic acid-1-methylethyl ester was dissolved in a mixture of 230 ml of trifluoroacetic acid and 23 ml of anisole at -10° C. Stirring was continued at -2°C for 30 minutes. After evaporation of the trifluoroacetic acid solution under vacuum at low temperature (10-20°C), the oily residue was dissolved in 350 ml of anhydrous ether, whereupon crystallization of the trifluoroacetate salt began immediately. Placing the ether mixture in a refrigerator led to an increased yield. After filtering off, the title compound was washed 2 times with anhydrous ether and then with petroleum ether (40-60°C), whereby after drying in a desiccator (P20^) 18 g of product were obtained; mp. 12 5.5°C. ;D) [3S-[3a(Z),43]]-[[3-[[(2-amino-4-thiazolyl)(methoxyimino)-acetyl]amino]-4-methyl-2-oxo-1- Azetidinyl]oxy]acetic acid-1-methylethyl ester ;While stirring, 5.8 g of anhydrous triethylamine was dissolved in 50 ml of anhydrous dimethylformamide, added dropwise to a solution of ;17.5 g of (3S-trans)-[[3-amino-4 -methyl-2-oxo-1-azetidinyl]-oxy]acetic acid-1-methylethyl ester-trifluoroacetate (0.053 mol) and ;16.9 g (Z)-2-amino-α-(methoxyimino)-4-thiazoleacetic acid-1 -hydroxybenzotriazole ester (0.053 mol) in 200 ml of dimethylformamide cooled to 0°C. After 2 hours (on completion of the triethylamine addition) the temperature of the reaction mixture was slowly allowed to rise to 20°C. At this temperature, stirring was continued for a further 4 hours. Dimethylformamide was removed under vacuum and the remaining oil taken up in ethyl acetate and shaken with ice-cold aqueous sodium bicarbonate (1N) and then with ice-cold water. The ethyl acetate layer which was dried with Na 2 SO 4 was evaporated under vacuum to 18.8 g of the title compound. Chromatography on silica gel with tetrahydrofuran/ethyl acetate (1:1) gave a pure product; m.p. 87-95°C decomp. ;Example 91 ;[3S-[3a(Z),43]]-[[3-[[(2-amino-4-thiazolyl)(methoxyimino)-acetyl]amino]-4-methyl-2-oxo-1 -azetidinyl]oxy]acetic acid-2-propenyl ester ;A) (3S-trans)-t[3-[(t-butyloxycarbonyl)amino]-2-methyl-4-oxo-1- azetidinyl]oxy]acetic acid- 2- propenyl ester; A solution of 17.3 g of (3S-trans)-3-(t-butyloxycarbonyl-amino)-1-hydroxy-4-methyl-2-azetidinone and 12.9 g of chloroacetic acid 2-propenyl ester in 350 ml of dry dimethylformamide was allowed to stand for 4 days at room temperature and was then worked up as described in example 90B. Yield 25.5 g crude ester. ;B) (3S-trans)-[[3-amino-4-methyl-2-oxo-1-azetidinyl]oxy]-acetic acid- 2- propenyl ester- trifluoroacetate ; 25.5 g of the crude (3S-trans) - f[3-[(t-butyloxycarbonyl)-amino]-4-methyl-2-oxo-1-azetidinyl]oxy]acetic acid-2-propenyl-ester was added to a stirred mixture of 200 ml of trifluoroacetic acid and 20 ml of anisole cooled to -10°C. After reaction for 25 minutes at -2°C, the excess of trifluoroacetic acid was removed under vacuum at a temperature varying from 20 to 25°C. The oily residue was taken up in 250 ml of anhydrous ether and placed in a refrigerator. The crystallized title compound was then filtered off, washed 2 times with anhydrous ether and finally with petroleum ether (40-60°C) and dried in a desiccator over P2°5', which resulted in 17.7 g of product; m.p. 112-113°C. ;C) [3S-[3a(Z),43]]-[[3-[[(2-amino-4-thiazolyl)(methoxyimino)-acetyl]amino]-4-methyl-2-oxo-1- azetidinyl]oxy]acetic acid 2-propenyl ester; To a stirred mixture of 17.4 g of (3S-trans)-[[3-amino-4-methyl-2-oxo-1-azetidinyl]oxy]acetic acid 2-propenyl ester -trifluoroacetate (0.053 mol) and 16.9 g of (Z)-2-amino-α-(methoxyimino)-4-thiazoleacetic acid-1-hydroxybenzotriazole ester in 200 ml of dimethylformamide, cooled to 0°C, was added portionwise 5, 8 g of triethylamine in 40 ml of anhydrous dimethylformamide. The temperature of the solution was then maintained at 5°C for 1 hour and then at 10°C for 2 hours, after which the mixture was allowed to stand at room temperature overnight. The processing was carried out as described in example 90D. Yield 18 g; m.p. 75-80°C decomp. ;Example 92 ;[3S-[3a(Z),43]]~[[3-[[(2-amino-4-thiazolyl)(methoxyimino)-acetyl]amino]-4-methyl-2-oxo-1 -azetidinyl]oxy]acetic acid-2-propynyl ester; A) (3S-trans)-[[3-[(t-butyloxycarbonyl)amino]-4-methyl-2-oxo-1- azetidinyl]oxy]acetic acid- 2- propynyl ester ; By following the procedure in Example 91A, but with chloroacetic acid 2-propynyl ester (1.7 g) instead of chloroacetic acid 2-propenyl ester, 2.2 g of the title compound were obtained in the form of an oil which was used in the next step without purification. ;B) (3S-trans)-[[3-amino-4-methyl-2-oxo-1-azetidinyl]oxy]-acetic acid-2-propynyl ester- trifluoroacetate ;Removal of the protecting group of the compound obtained above (2, 2 g) was obtained with trifluoroacetic acid/anisole (25 mL/2.5 mL) using the procedure of Example 92B. Yield 1.7 g; m.p. 106-107°C. ;C) [3S-[3a(Z),43]]-t[3-[[(2-amino-4-thiazolyl)(methoxyimino)acetyl]amino]-4-methyl-2-oxo-1-azetidinyl ]oxy]-acetic acid-2-propynyl ester; 1.6 g of (3S-trans)-[[3-amino-4-methyl-2-oxo-1-azetidinyl]-oxy]acetic acid-2-propynyl ester-trifluoroacetate was coupled with 1.6 g of (Z)-2-amino-α-(methoxyimino)-4-thiazoleacetic acid-1-hydroxybenzotriazole ester as described in Example 92C. Chromatography on silica gel with tetrahydrofuran/ether (1:1) afforded 1.1 g of the title compound; m.p. 69-75°C decomp. ;Example 9 3 ;[3S-[3a(Z),43]]-[[3-[[(2-amino-4-thiazolyl)(methoxyimino)-acetyl]amino]-4-methyl-2-oxo- 1-azetidinyl]oxy]acetic acid propyl ester ;A) (3S-trans)-[[3-[(t-butyloxycarbonyl)amino]-4-methyl-2-oxo-1- azetidinyl]oxy]acetic acid propyl ester ;With following the procedure of Example 91A, but with chloroacetic acid propyl ester (3.0 g) instead of chloroacetic acid 2-propenyl ester, 4.2 g of the title compound was obtained; mp. 72°C. ;B) (3S-trans)-[[3-amino-4-methyl-2-oxo-1-azetidinyl]oxy]-acetic acid-propyl ester-trifluoroacetate ;Treatment of the preceding ester (4.2 g) with 50 ml of trifluoroacetic acid and 5 ml of anisole, as indicated in Example 91B, gave 3.3 g of the title compound. ;C) [3S-[3a(Z),43]]~[[3-[[(2-amino-4-thiazolyl)(methoxyimino)-acetyl]amino]-4-methyl-2-oxo-1- azetidinyl]oxy]acetic acid propyl ester; 4.88 ml of MSTFA (95%) (2.5 mmol) was added to a suspension of 3.3 g of (3S-trans)-[[3-amino-4-methyl-2 -oxo-1-azetidinyl]oxy]acetic acid propyl ester trifluoroacetate in 60 ml of dry acetonitrile at 0°C. Stirring was continued until the trifluoroacetate had dissolved. The clear solution was allowed to stand overnight and after evaporation of acetonitrile under vacuum, the remaining oil (3.39 g) was dissolved in 40 ml of dry tetrahydrofuran and 2.96 g of (Z)-2-amino-α-(methoxyimino) was added -4-thiazoleacetic acid-1-hydroxybenzotriazole ester (8.44 mmol) and the mixture stirred for 4 hours at room temperature. The solvent was removed under vacuum at 30°C and the residue taken up in ethyl acetate, shaken with ice-cold aqueous sodium bicarbonate (1N) and then with ice water. The ethyl acetate layer was dried with Na 2 SO 4 and the title compound (4 g oil) chromatographed on silica gel with ethyl acetate. Yield 3.1 g; m.p. 68-71°C decomp. ;Example 94 ;[3S-[3a(Z),43]]-[[3-[[(2-amino-4-thiazolyl)(methoxyimino)-acetyl]amino]-4-methyl-2-oxo-1 -azetidinyl]oxy]acetic acid-2- chloroethyl ester ;A) (3S-trans)-[[3-[(t-butyloxycarbonyl)amino]-4-methyl-2- oxo- 1- azetidinyl]oxy]acetic acid- 2- Chloroethyl ester ; By following the procedure in Example 91A, but with chloroacetic acid 2-chloroethyl ester (4.32 g) instead of chloroacetic acid 2-propenyl ester, 5.2 g of the title compound was obtained (ethyl acetate/ether 1:1 was used as eluent in chromatography on silica gel). ;B) (3S-trans)-[[3-amino-2-methyl-4-oxo-1-azetidinyl]oxy]-acetic acid- 2-chloroethyl ester- trifluoroacetate ; Using trifluoroacetic acid and anisole (as described in example 91B ) the title compound was prepared from the preceding t-butyloxycarbonyl-protected amino derivative ; Yield 4.19 g. ; C) [2S-[2a,33(Z)]]-[[3-[[(2-amino-4-thiazolyl )(methoxyimino)-acetyl]amino]-2-methyl-4-oxo-1-azetidinyl]oxy]acetic acid-2-chloroethyl ester; 2.0 g (3S-trans)-[[3-amino-4-methyl- 2-oxo-1-azetidinyl]-oxy]acetic acid-2-chloroethyl ester-trifluoroacetate was coupled with 1.89 g of (Z)-2-amino-α-(methoxyimino)-4-thiazoleacetic acid-1-hydroxybenzotriazole as described in Example 91C, whereby 1.66 g of the title compound was obtained (tetrahydrofuran/ether 1:1) was used as eluent in chromatography on silica gel); m.p. 84-85°C decomp. ;Example 9 5 ;[3S-[3a(Z),4 3]]-[[3-[[(2-amino-4-thiazolyl)(methoxyimino)-acetyl]amino]-4-methyl-2-oxo -1-azetidinyl]oxy]acetic acid cyclohexyl ester ;(3S-trans)-[[3-[(t-butyloxycarbonyl)amino]-4-methyl-2-oxo-1-azetidinyl]oxy]acetic acid cyclohexyl ester (2, 23 g) prepared analogously to the method in example 91A, was dissolved in a solution of 25 ml of trifluoroacetic acid and 2.5 ml of anisole at -10°C. The mixture was evaporated under vacuum 25 minutes later and the residue stirred with ether, filtered off and dried over ? 2^5 grainless crystals of (3S)-[[3-amino-4-methyl-2-oxo-1-azetidinyl]oxy]acetic acid cyclohexyl ester trifluoroacetate salt (yield 1.53 g). The salt (1.5 g) was suspended in 30 ml of acetonitrile and at 0°C MSTFA (2.37 ml) was added and the solution left overnight. After evaporation under vacuum, the residue (1.75 g) was dissolved in dry tetrahydrofuran (25 ml), and 1.4 g of (Z)-2-amino-α-(methoxyimino)-4-thiazoleacetic acid-1-hydroxybenzotriazole ester was added and the mixture was stirred at room temperature for 4 hours. Tetrahydrofuran was removed under vacuum at 30°C and the residue taken up in ether, washed with ice-cold aqueous NaHCO 3 (1N) and 2 times with cold water. The dried ethyl acetate layer was evaporated under vacuum and the resulting oil (2.14 g) chromatographed on silica gel with ethyl acetate to give 1.58 g of the title compound; mp. 8 5-90°C decomp. ;Example 96 ;[3S-[3a(Z),43]]-[[3-[[(2-amino-4-thiazolyl)(methoxyimino)-acetyl]amino]-4-methyl-2-oxo-1 -azetidinyl]oxy]acetic acid cyclopentyl ester ; By following the procedure in example 95, but with (3S-trans)-[[3-[(t-butyloxycarbonyl)amino]-4-methyl-2-oxo-1-azetidinyl] oxy]acetic acid cyclopentyl ester instead of (3S-trans)-[[3-[(t-butyloxycarbonyl)amino]-4-methyl-2-oxo-1-azetidinyl]oxy]acetic acid cyclohexyl ester, the title compound was obtained; m.p. 90-95°C decomp. ;Example 9 7 ;[3S-[3a(Z),43]]-[[3-[[(2-amino-4-thiazolyl)(methoxyimino)-acetyl]amino]-4-methyl-2-oxo- 1-azetidinyl]oxy]acetic acid cyclopentyl methyl ester ;(3S-trans)-[[3-[(t-butyloxycarbonyl)amino]-4-methyl-2-oxo-1-azetidinyl]oxy]acetic acid cyclopentylmethyl ester, ;which can obtained from (3S-trans)-3-(t-butyloxycarbonylamino-1-hydroxy-4-methyl-2-azetidinone and chloroacetic acid cyclopentyl methyl ester) was deprotected and coupled to the title compound by following the procedure described in Example 90B to 90D; mp 73-80°C decomp.; Example 98 ;[3S-[3a(Z),43]]-[[3-t[(2-amino-4-thiazolyl)(methoxyimino)-acetyl] amino]-4-methyl-2-oxo-1-azetidinyl]oxy]acetic acid-2, 2- dimethylpropyl ester ;(3S-trans)-[[3-[(t-butyloxycarbonyl)amino]-4-methyl-2- Oxo-1-azetidinyl]oxy]acetic acid-2,2-dimethylpropyl ester was converted via the corresponding trifluoroacetate salt to the title compound (m.p. 74-76°C decomp.) by using the procedure in Examples 91A to 91C. ;Example 99 ;[3S- [3a(Z),43]]-[[3- [[(2-amino-4-thiazolyl)(methoxyimino)-acety1]amino]-4-methyl-2-oxo-1-azetidinyl]oxy]acetic acid-2-ethylbutyl ester; By following the procedure in Examples 91A to 91C, (3S-trans)-[[3-[(t-butyloxycarbonyl)amino]-4-methyl-2-oxo-1-azetidinyl]oxy]acetic acid-2-ethylbutyl ester was converted via the trifluoroacetate salt to the title ester; m.p. 56-60°C decomp. ;Example 100 ;[3S-[3a(Z),43]]-[[3-[[(2-amino-4-thiazolyl)(methoxyimino)-acetyl]amino]-4-methyl-2-oxo-1 -azetidinyl]oxy]acetic acid-2,2,2-trifluoroethyl ester; By following the procedure in Example 90, (3S-trans)-[[3-[(t-butyloxycarbonyl)amino]-4-methyl-2-oxo -1-azetidinyl]-oxy]acetic acid-2,2,2-trifluoroethyl ester deacylated to the corresponding trifluoroacetate salt and then coupled with (Z)-2-amino-α-(methoxyimino)-4-thiazoleacetic acid-1-hydroxy-benzotriazole ester to the title compound; m.p. 75-81°C decomp. ;Example 101 ;[3S-[3a(Z),43]]-[[3[[(5-amino-1,2,4-thiadiazol-3-yl)(methoxyimino)acetyl] amino]- 4- methyl - 2-oxo-1-azetidinyl]oxy]acetic acid ;(3S-trans)-[[3-[(butyloxycarbonyl)amino]-4-methyl-2-oxo-1-azetidinyl]oxy]acetic acid diphenylmethyl ester (15 g ; 34 mmol) was dissolved in a solution of 112 ml of trifluoroacetic acid and 11.2 ml of anisole at -10°C. The mixture was evaporated under vacuum 10 minutes later, after which the residue was stirred with ether, filtered off and dried over P2°5t:L1 7' 3 g crystals of (3S)-[[3-amino-4-methyl-2-oxo-1 -azetidinyl]oxy]acetic acid trifluoroacetate salt. The salt (7.3 g) was suspended in 30 mL of dry acetonitrile, MSTFA (3.34 mL) was added and stirring continued for 1 hour. After evaporation under vacuum, the residue was dissolved in dry tetrahydrofuran, whereupon (Z)-5-amino-1,2,4-thiadiazol-3-yl-α-(methoxyimino)acetic acid-1-hydroxybenzotriazole ester (2.0 g) was added and the mixture stirred overnight at room temperature and evaporated under vacuum. After addition of ether, the crude silylated product was decomposed with 0.5 ml of methanol. The undissolved product was filtered off, dissolved in tetrahydrofuran and chromatographed on silica gel with ethyl acetate/ether 1:1, whereby the title compound was obtained; m.p. 165-166°C. ;Example 102 ;[3S-[3a(Z),43]]-[[3-[[(5-amino-1,2,4-thiadiazol-3-yl)(methoxyimino)acetyl]amino]-4- methyl-2-oxo-1-azetidinyl]oxy]acetic acid- 1- methylethyl ester; 1.35 g (3S-trans)[[3-amino-4-methyl-2-oxo-1-azetidinyl]-oxy]acetic acid- 1-Methyl ethyl ester trifluoroacetate (4.1 mmol) was suspended in 25 mL of dry acetonitrile. MSTFA (2.28 mL) was added at 0°C, whereupon stirring was continued for 30 minutes and the solution was left overnight at room temperature. After evaporation under vacuum, the residue (1.92 g) was dissolved in 13 ml of dry tetrahydrofuran, added (Z)-5-amino-1,2,4-thiadiazol-3-yl-α-(methoxyimino)acetic acid-1- hydroxybenzotriazole ester (1.75 g) and the mixture stirred overnight at room temperature and evaporated under vacuum. The residue was taken up in ethyl acetate, washed with ice-cold aqueous NaHCO 3 (1N) and then with ice water. The ethyl acetate layer was dried with Na 2 SO 4 and chromatographed on silica gel with ethyl acetate as eluent. Yield of the title compound was 1.10 g; m.p. 83-85°C. ;Example 103 ;[3S-[3a(Z),43]]-[[3-[[(6-amino-2-pyridinyl)(methoxyimino)-acetyl]amino]-4-methyl-2-oxo-1 -azetidinyl]oxy]acetic acid monosodium salt; By following the procedure in example 101, but with (Z)-6-amino-2-pyridinyl-α-(methoxyimino)acetic acid-1-hydroxy-benzotriazole ester instead of (Z)- 5-amino-1,2,4-thiazdl-3-yl-α-(methoxyimino)acetic acid-1-hydroxybenzotriazole ester, the free acid of the title compound was obtained. This was suspended in ice-cold water, pH adjusted to 6.5 with 1N sodium hydroxide and the clear solution freeze-dried, whereby the salt was obtained; m.p. 14 0°C decomp. ;Example 104 ;(3S-trans)-[[3-[[[(2,6-dichloro-4-pyridinyl)thio]acetyl]amino]-4- methyl- 2-oxo-1- azetidinyl] oxyacetic acid monosodium salt ;By following the procedure in example 103, but with 2,6-dichloro-4-pyridinylthioacetic acid-4-nitrophenyl ester instead of (Z)-6-amino-2-pyridinyl-α-(methoxyimino)acetic acid-1-hydroxy- benzotriazole ester, the title compound was obtained; mp. 9 7-100°C decomp. ;Example 105 ;[3S-[3a(Z),43]]-[[3-[[(2-amino-4-thiazolyl)(methoxyimino)-acetyl]amino]-4-methyl-2-oxo-1 -azetidinyl]oxy]acetic acid-1-[[(cyclohexyloxy)carbonyl]oxy]ethoxy ester ;[3S-[3a(Z),43]]-[[3-[[(2-amino-4-thiazolyl)(methoxyimino )-acetyl]amino]-4-methyl-2-oxo-azetidinyl]oxy]acetic acid mono-potassium salt (0.40 g) was dissolved in 10 ml of dry dimethylformamide. α-Chloroethyl cyclopentyl carbonate (0.20 g) and 0.083 g of potassium iodide were added at room temperature and stirred at room temperature for 2 days. The solvent was evaporated in vacuo and the residue taken up in ethyl acetate, washed successively with water, 1N NaHCO 3 solution, water and then dried (Na 2 SO 4 ). After removal of the solvent in vacuo, the resulting oil (0.34 g) was purified by chromatography on silica gel with a mixture of tetrahydrofuran/ether (1:1) as eluent, whereby 0.31 g of the oily title compound, which crystallized after treatment with water, was obtained, mp 85-90°C decomp.; Example 106 ;[3S-[3a(Z) ,43]]-[[3-[[(2-amino-4-thiazolyl) (methoxyimino)-acetyl]amino]-4-methyl-2-oxo-1- azetidinyl]oxy]acetic acid-1-[(ethoxycarbonyl)oxy]ethyl ester; By following the procedure in example 105, but with α-iodoethyl ethyl carbonate instead of α-chloroethyl cyclopentyl carbonate, the title compound was obtained; m.p. 120- 125°C decomp.; Example 107 ;[3S-[3a(Z),43]]-t[[[3-[[(2-amino-4-thiazolyl)(methoxyimino)-acetyl]amino]-4- methyl-2-oxo-1-azetidinyl]oxy]acetyl]oxy]-acetic acid- 1, 1- dimethylethyl ester; To a solution of [3S-[3a(Z ),43]]-tt3-[[(2-amino-4-thiazolyl)(methoxyimino)acetyl]amino]-4-methyl-2-oxo-1-azetidinyl]oxy]acetic acid sodium salt in 50 ml of dry dimethylformamide was 4.14 g of t-butyl iodoacetate were added dropwise. Stirring was continued at room temperature for 3 hours. The solvent was evaporated under vacuum at room temperature and the residue taken up in ethyl acetate, washed successively with ice-cold water, ice-cold aqueous NaHCO^ and ice-cold saline and then dried over CaSO^. After filtration and removal of the solvent under vacuum, the residue was chromatographed on silica gel with ethyl acetate as eluent, whereby 2.9 g of the title compound was obtained; m.p. 77°C decomp. ;Example 108 ;[3S[3ot(Z) ,4a] ]-[ [ 3-[ [ (2-amino-4-thiazolyl) (methoxyimino)-acetyl]amino]-4-methyl-2-oxo-1- azetidinyl]oxy]acetic acid monosodium salt ;A solution of 0.33 g of triethylamine in 5 ml of dry dimethylformamide was dropped into a solution of 0.33 g of (3S-cis)-[(3-amino-4-methyl-2- oxo-1-azetidinyl)oxy]acetic acid trifluoroacetate salt and 0.35 g of (Z)-2-amino-2-(methoxyimino)-4-thiazole-acetic acid-1-hydroxybenzotriazole ester in 20 ml of dimethylformamide at 0°C, after which the stirring was continued for 3 hours at room temperature. The solvent was then evaporated under vacuum and the residue suspended in 10 ml of n-butanol and a solution of 0.55 g of sodium 2-ethyl hexanoate in 10 ml of n-butanol was added. The mixture was stirred for 4 hours at room temperature. The precipitate was filtered off under suction, washed with n-butanol and ether and then dried under vacuum over P2<")5*After chromatography (reversed phase) on HP-20 resin with water as eluent, followed by lyophilization of appropriate fractions, the title compound was obtained; yield 0.14 g; decomp.>170°C.

Eksempel 109Example 109

[3S- [3a(Z) ,4a] ] -2[ [ [ 1 - (2-amino-4-tiazoly 1) -2-[ [ 1 - (karboksy-metoksy)-4-metyl-2-okso-3-azetidinyl]amino]-2-oksoetyliden]-amino] oksy]- 2- metylpropansyre- dinatriumsalt [3S- [3a(Z) ,4a] ] -2[ [ [ 1 - (2-amino-4-thiazoly 1)-2-[ [ 1 - (carboxy-methoxy)-4-methyl-2-oxo- 3-azetidinyl]amino]-2-oxoethylidene]-amino]oxy]- 2- methylpropanoic acid disodium salt

A) [3S-[3a(Z),4a]]-2[[[1-(2-amino-4-tiazolyl)-2-[[1-(karboksymetoksy)-4-metyl-2-okso-3-azetidinyl]amino]-2-oksoety liden] amino.]oksy] -2-metylpropansyre-difenylmetylester-mononatriumsalt A) [3S-[3a(Z),4a]]-2[[[1-(2-amino-4-thiazolyl)-2-[[1-(carboxymethoxy)-4-methyl-2-oxo-3 -azetidinyl]amino]-2-oxoethylidene]amino.]oxy]-2-methylpropanoic acid diphenylmethyl ester monosodium salt

1,3 ml MSTFA ble tilsatt til en suspensjon av 0,63 g (3S-cis)-[(3-amino-4-metyl-2-okso-1-azetidinyl)oksy]eddiksyre-trifluoracetatsalt i 10 ml tørr acetonitril ved 0°C og omrøringen fortsatt i 30 minutter ved romtemperatur. Etter inndampning under vakuum ble residuet løst i 15 ml tørr tetrahydrofuran og denne løsning tilsatt ved 0°C til en blanding av 0,97 g (Z)-2-amino-a-[[2-(difenylmetoksy)-1,1-dimetyl-2-oksoetoksy]imino]-4-tiazoleddiksyre, 0,34 g 1-hydroksybenzotriazol og 0,45 g dicykloheksylkarbodiimid i 1.3 ml of MSTFA was added to a suspension of 0.63 g of (3S-cis)-[(3-amino-4-methyl-2-oxo-1-azetidinyl)oxy]acetic acid trifluoroacetate salt in 10 ml of dry acetonitrile at 0°C and stirring continued for 30 minutes at room temperature. After evaporation under vacuum, the residue was dissolved in 15 ml of dry tetrahydrofuran and this solution added at 0°C to a mixture of 0.97 g of (Z)-2-amino-α-[[2-(diphenylmethoxy)-1,1- dimethyl-2-oxoethoxy]imino]-4-thiazoleacetic acid, 0.34 g of 1-hydroxybenzotriazole and 0.45 g of dicyclohexylcarbodiimide in

10 ml tetrahydrofuran som var blitt omsatt i 2 timer ved 50°C. Etter omrøring over natten ved romtemperatur, ble presipitatet inndampet under vakuum. Residuet ble deretter tilsatt iskaldt vann og eter og pH justert til 6,5 med 5% natriumbikarbonat-løsning. Det organiske lag og uløselige produkter ble skilt og den vandige fase frysetørket. Søylekromatografi på HP-20 resin med vann og vann/aceton (7:3) som eluent, førte til 0,56 g rent produkt; smp. >168°C dekomp. B) [3S-[3a(Z),4a]]-2-[[[1-(2-amino-4-tiazolyl)-2-[[1-(karboksymetoksy)-4-metyl-2-okso-3-azetidinyl]amino]-2-oksoetyliden] amino] oksy]- 2- metylpropansyre- dinatriumsalt 0,29 g (0,47 mmol) frysetørket [3S-[3a(Z),4a]]-2-[[[1-(2-amino-4-tiazolyl)-2-[[1-(karboksymetoksy)-4-metyl-2-okso-3-azetidinyl]amino]-2-oksoetyliden]amino]oksy]-2-metylpropansyre-dif eny lmetylester-mononatriumsalt ble suspendert i en løsning av 2,1 ml trifluoreddiksyre og 0,21 ml anisol ved -10°C. Etter omrøring i 10 minutter ved 0°C ble trifluoreddiksyren fjernet under vakuum (badtemperatur <5°C). Eter og iskaldt vann ble tilsatt og pH justert til 6,5 med 5% natriumbikarbonat. Etter frysetørking av det vandige lag, ble råproduktet kromatografert på HP-2 0 med vann som eluent; 10 ml of tetrahydrofuran which had been reacted for 2 hours at 50°C. After stirring overnight at room temperature, the precipitate was evaporated under vacuum. The residue was then added with ice-cold water and ether and the pH adjusted to 6.5 with 5% sodium bicarbonate solution. The organic layer and insoluble products were separated and the aqueous phase freeze-dried. Column chromatography on HP-20 resin with water and water/acetone (7:3) as eluent gave 0.56 g of pure product; m.p. >168°C decomp. B) [3S-[3a(Z),4a]]-2-[[[1-(2-amino-4-thiazolyl)-2-[[1-(carboxymethoxy)-4-methyl-2-oxo- 3-azetidinyl]amino]-2-oxoethylidene]amino]oxy]-2-methylpropanoic acid disodium salt 0.29 g (0.47 mmol) freeze-dried [3S-[3a(Z),4a]]-2-[[[ 1-(2-amino-4-thiazolyl)-2-[[1-(carboxymethoxy)-4-methyl-2-oxo-3-azetidinyl]amino]-2-oxoethylidene]amino]oxy]-2-methylpropanoic acid- The diphenyl methyl ester monosodium salt was suspended in a solution of 2.1 ml of trifluoroacetic acid and 0.21 ml of anisole at -10°C. After stirring for 10 minutes at 0°C, the trifluoroacetic acid was removed under vacuum (bath temperature <5°C). Ether and ice-cold water were added and the pH adjusted to 6.5 with 5% sodium bicarbonate. After lyophilization of the aqueous layer, the crude product was chromatographed on HP-20 with water as eluent;

utbytte 0,16 g; dekomp. >6 0°C.yield 0.16 g; decomp. >60°C.

Eksempel 110 Example 110

[3S-[3a(Z),43]]-[[3-[t(2-amino-4-tiazolyl)(metoksyimino)-acetyl]amino]-4-mety1-2-okso-1-azetidinyl]oksy]eddiksyre-[ (3-pentyloksy) karbonyl] metylester [3S-[3α(Z),43]]-[[3-[t(2-amino-4-thiazolyl)(methoxyimino)-acetyl]amino]-4-methyl-2-oxo-1-azetidinyl]oxy ]acetic acid-[ (3-pentyloxy) carbonyl] methyl ester

A) Bromeddiksyre-[( 3- pentyloksy) karbonyl] metylester A) Bromoacetic acid-[(3-pentyloxy)carbonyl] methyl ester

Bromeddiksyre-3-pentylester (330 g, 1,6 mol) ble løst i 300 ml dimetylformamid. Bromeddiksyre-kaliumsalt (142 g) ble tilsatt porsjonsvis under omrøring og omrøringen fortsatt over natten. Blandingen ble deretter heilt over i 1 liter iskaldt vann og tilsatt 500 ml eter. Etter vasking med vann og NaHCO^-løsning og tørking med MgSO^, ble eteren fordampet. Bromoacetic acid 3-pentyl ester (330 g, 1.6 mol) was dissolved in 300 ml of dimethylformamide. Bromoacetic acid-potassium salt (142 g) was added portionwise with stirring and stirring continued overnight. The mixture was then poured into 1 liter of ice-cold water and 500 ml of ether was added. After washing with water and NaHCO 3 solution and drying with MgSO 3 , the ether was evaporated.

Ved destillasjon ble 156 g av utgangsesteren gjenvunnet og 103,5 g tittelforbindelse oppnådd (kokepunkt 160-162°C ved By distillation, 156 g of the starting ester was recovered and 103.5 g of the title compound was obtained (boiling point 160-162°C at

12 mm Hg).12 mm Hg).

B) (3S-trans)-[[3-[(t-butyloksykarbonyl)amino]-4-metyl-2-okso-1-azetidinyl]oksy]eddiksyre-[(3-pentyloksy)karbonyl]-metylester B) (3S-trans)-[[3-[(t-butyloxycarbonyl)amino]-4-methyl-2-oxo-1-azetidinyl]oxy]acetic acid-[(3-pentyloxy)carbonyl]-methyl ester

(3S-trans)-3-[(t-butyloksykarbonyl)amino]-1-hydroksy-4-metyl-2-azetidinon (21,6 g) ble løst i 250 ml dimetylformamid. Ved 0°C ble 26,7 g bromeddiksyre-[(3-pentyloksy)-karbonyllmetylester og deretter 17 ml trietylamin tilsatt. Blandingen ble omrørt over natten og dimetylformamidet fordampet under vakuum. Det oljeaktige residuum ble løst i 300 ml etylacetat, vasket med iskald NaHCC^-løsning og deretter 3 ganger med isvann. Etter tørking over MgSO^, ble løsnings-midlet fordampet under vakuum, hvorved 35,6 g av tittelforbindelsen ble oppnådd i form av en olje. (3S-trans)-3-[(t-butyloxycarbonyl)amino]-1-hydroxy-4-methyl-2-azetidinone (21.6 g) was dissolved in 250 ml of dimethylformamide. At 0°C, 26.7 g of bromoacetic acid-[(3-pentyloxy)-carbonyl methyl ester and then 17 ml of triethylamine were added. The mixture was stirred overnight and the dimethylformamide evaporated under vacuum. The oily residue was dissolved in 300 ml of ethyl acetate, washed with ice-cold NaHCl solution and then 3 times with ice water. After drying over MgSO 4 , the solvent was evaporated under vacuum, whereby 35.6 g of the title compound was obtained in the form of an oil.

C) (3S-trans)-[(3-amino-4-metyl-2-okso-1-azetidinyl)oksy]-eddiksyre-[( 3- pentyloksy) karbonyl] metylester C) (3S-trans)-[(3-amino-4-methyl-2-oxo-1-azetidinyl)oxy]-acetic acid-[(3-pentyloxy)carbonyl] methyl ester

(3S-trans)-[[3-[(t-butyloksykarbonyl)amino]-4-metyl-2-okso-1-azetidinyl]oksy]eddiksyre-[(3-pentyloksy)karbonyl]-metylester ble løst i diklormetan. Ved -10°C ble 50 ml trifluoreddiksyre langsomt tilsatt. Temperaturen ble holdt ved -10°C i 20 minutter og løsningsmidlet fordampet under vakuum, hvorved 13 g av tittelforbindelsen ble oppnådd som en olje. (3S-trans)-[[3-[(t-butyloxycarbonyl)amino]-4-methyl-2-oxo-1-azetidinyl]oxy]acetic acid-[(3-pentyloxy)carbonyl]-methyl ester was dissolved in dichloromethane. At -10°C, 50 ml of trifluoroacetic acid was slowly added. The temperature was kept at -10°C for 20 minutes and the solvent was evaporated under vacuum, whereby 13 g of the title compound was obtained as an oil.

D) [3S-[3a(Z),43]]-[[3-[[(2-amino-4-tiazolyl)(metoksyimino)-acetyl]amino]-4-mety1-2-okso-1-azetidinyl]oksy]eddiksyre-[ (3-pentyloksy) karbonylJmetylester D) [3S-[3a(Z),43]]-[[3-[[(2-amino-4-thiazolyl)(methoxyimino)-acetyl]amino]-4-methyl-2-oxo-1-azetidinyl ]oxy]acetic acid-[(3-pentyloxy)carbonyl Jmethyl ester

(Z)-2-amino-a-(metoksyimino)-4-tiazoleddiksyre (6 g)(Z)-2-amino-α-(methoxyimino)-4-thiazoleacetic acid (6 g)

ble løst i 100 ml dimetylformamid og tilsatt 5 ml trietylamin og, etter avkjøling til -25°C, tilsatt 6,2 ml difenylfosfo-kloridat. Blandingen ble omrørt ved -25°C i 50 minutter og deretter tilsatt til en løsning fremstillet av 13 g (3S-trans)-[(3-amino-4-metyl-2-okso-1-azetidinyl)oksy]eddiksyre[(3-pentyloksy)karbonyl]metylester, 21 ml trietylamin og 100 ml dimetylformamid ved -25°C. Reaksjonsblandingen ble omrørt ved was dissolved in 100 ml of dimethylformamide and added with 5 ml of triethylamine and, after cooling to -25°C, added with 6.2 ml of diphenylphosphochloridate. The mixture was stirred at -25°C for 50 minutes and then added to a solution prepared from 13 g of (3S-trans)-[(3-amino-4-methyl-2-oxo-1-azetidinyl)oxy]acetic acid[( 3-pentyloxy)carbonyl]methyl ester, 21 ml of triethylamine and 100 ml of dimethylformamide at -25°C. The reaction mixture was stirred at

-25°C i 2,5 timer. Løsningsmidlet ble fordampet under vakuum og residuet løst i 4 00 ml etylacetat, vasket med isvann, NaHCO^-løsning og isvann, tørket (MgSO^) og igjen inndampet, hvorved tittelforbindelsen ble oppnådd i form av et fast skum som ble -25°C for 2.5 hours. The solvent was evaporated under vacuum and the residue dissolved in 400 ml of ethyl acetate, washed with ice water, NaHCO 3 solution and ice water, dried (MgSO 4 ) and again evaporated, whereby the title compound was obtained in the form of a solid foam which was

behandlet med heksan. Produktutbyttet var 8,7 g; renhet 83% treated with hexane. The product yield was 8.7 g; purity 83%

(HPLC); smp. 76-80°C.(HPLC); m.p. 76-80°C.

Eksempel 111 Example 111

[3S-[3a(Z),43]]-[[3-[[(2-amino-4-tiazolyl)(metoksyimino)-acety1]amino]-4-metyl-2-okso-1-azetidinyl]oksy]eddiksyre-1-[( 3- pentyloksy) karbonyl] etylester [3S-[3a(Z),43]]-[[3-[[(2-amino-4-thiazolyl)(methoxyimino)-acety1]amino]-4-methyl-2-oxo-1-azetidinyl]oxy ]acetic acid-1-[(3-pentyloxy)carbonyl]ethyl ester

A) L- melkesyre- 3- pentylesterA) L- lactic acid- 3- pentyl ester

En blanding av 180 g L-melkesyre, 528 g 3-pentanol ogA mixture of 180 g of L-lactic acid, 528 g of 3-pentanol and

1 ml kons. E^ SO^ ble kokt under tilbakeløp i et Dean-Stark apparat inntil dannelsen av vann opphørte (ca 3 timer). Blandingen ble vasket med vann, NaHCO^- og salt-oppløsning, tørket (MgSO^) og destillert, hvorved tittelforbindelsen ble oppnådd; kokepunkt 79-81°C ved 15 mm Hg. 1 ml conc. E^SO^ was refluxed in a Dean-Stark apparatus until the formation of water ceased (about 3 hours). The mixture was washed with water, NaHCO 4 and brine, dried (MgSO 4 ) and distilled to give the title compound; boiling point 79-81°C at 15 mm Hg.

B) L- bromeddiksyre- 1-[( 3- pentyloksy) karbonyl] etylester B) L-bromoacetic acid- 1-[(3-pentyloxy)carbonyl] ethyl ester

L-melkesyre-3-pentylester (47 g) ble løst i 150 mlL-lactic acid 3-pentyl ester (47 g) was dissolved in 150 ml

eter. Blandingen ble deretter tilsatt 36,6 ml dimetylfenylamin og avkjølt til -10°C, etterfulgt av tilsetning av 53 g brom-acetylbromid. Temperaturen ble holdt lavere enn 5°C og blandingen omrørt i flere timer ved romtemperatur. Reaksjonsblandingen ble heilt over i 500 ml isvann, hvorpå den organiske fase ble vasket med 2N H^PC^-løsning, NaHCO^-løsning og vann, tørket (MgSO^) og løsningsmidlet fordampet. Residuet ble vakuum-fraksjonert og førte til tittelforbindelsen i form av en farveløs væske med et kokepunkt på 146-148°C ved 15 mm Hg. ether. The mixture was then added with 36.6 ml of dimethylphenylamine and cooled to -10°C, followed by the addition of 53 g of bromoacetyl bromide. The temperature was kept lower than 5°C and the mixture stirred for several hours at room temperature. The reaction mixture was poured into 500 ml of ice water, after which the organic phase was washed with 2N H^PC^ solution, NaHCO^ solution and water, dried (MgSO^) and the solvent evaporated. The residue was vacuum fractionated to give the title compound as a colorless liquid, bp 146-148°C at 15 mm Hg.

C) [3S-[3a(Z),43]]-[[3-[[(2-amino-4-tiazolyl)(metoksyimino)-acetyl]amino]-4-metyl-2-okso-1-azetidinyl]oksy]eddiksyre-1-[( 3- pentyloksy) karbonyl] etylester C) [3S-[3a(Z),43]]-[[3-[[(2-amino-4-thiazolyl)(methoxyimino)-acetyl]amino]-4-methyl-2-oxo-1-azetidinyl ]oxy]acetic acid-1-[(3-pentyloxy)carbonyl]ethyl ester

Ved å følge fremgangsmåten i eksempel 110, punktene B,By following the procedure in Example 110, points B,

C og D, men med L-bromeddiksyre-1-[(3-pentyloksy)karbonyl]-etylester , ble tittelforbindelsen oppnådd. C and D, but with L-bromoacetic acid 1-[(3-pentyloxy)carbonyl]-ethyl ester, the title compound was obtained.

Claims (10)

1. Fremgangsmåte for fremstilling av 3-laktamer med en 1. Process for the production of 3-lactams with a substituent i 1-stillingen og en acylamino- eller eventuelt beskyttet aminosubstituent i 3-stillingen, eller en ester, eller et salt derav; hvor R<- og Rg er like eller forskjellige og hver står for hydrogen, alkyl, alkenyl, alkynyl, fenyl, substituert fenyl, cykloalkyl eller en 4-, 5-, 6- eller 7-leddet heterocyklus, eller R,, og R^ sammen med det karbonatom som de er knyttet til, utgjør cykloalkyl eller en 4-, 5-, 6- eller 7-leddet heterocyklus, eller en av R d c og Rb, er hydrogen og den annen azido, halogenmetyl, dihalogenmetyl, trihalogenmetyl, halogen, alkoksykarbonyl, alkenyl, alkynyl, 2-fenyletenyl, 2-fenyletynyl, karboksyl, -CH2~ X1 , - S- X^, -0-X2 , eller substituent in the 1-position and an acylamino or optionally protected amino substituent in the 3-position, or an ester, or a salt thereof; where R<- and Rg are the same or different and each represents hydrogen, alkyl, alkenyl, alkynyl, phenyl, substituted phenyl, cycloalkyl or a 4-, 5-, 6- or 7-membered heterocycle, or R,, and R ^ together with the carbon atom to which they are attached form cycloalkyl or a 4-, 5-, 6- or 7-membered heterocycle, or one of R d c and Rb is hydrogen and the other azido, halomethyl, dihalomethyl, trihalomethyl, halogen, alkoxycarbonyl, alkenyl, alkynyl, 2-phenylethenyl, 2-phenylethynyl, carboxyl, -CH2~ X1 , - S- X^, -0-X2 , or hvor X^ er azido, amino, hydroksy, alkanoylamino, fenylkarbonylamino, (substituert fenyl)karbonylamino, alkylsulfonyloksy, fenylsulfonyloksy, (substituert fenyl)-sulfonyloksy, fenyl, substituert fenyl, cyano, where X^ is azido, amino, hydroxy, alkanoylamino, phenylcarbonylamino, (substituted phenyl)carbonylamino, alkylsulfonyloxy, phenylsulfonyloxy, (substituted phenyl)sulfonyloxy, phenyl, substituted phenyl, cyano, -S-X2 , eller -0-X2 ; X2 er alkyl, substituert alkyl, fenyl, substituert fenyl, fenylalkyl, (substituert fenyl)alkyl, alkanoyl, fenylalkanoyl, (substituert fenyl)alkanoyl, fenyl-karbonyl, (substituert fenyl)karbonyl eller heteroarylkarbonyl; A er -CH=CH-, -(CH_) -, -CH -0-, -CH„-NH-, eller -CH -S-CH_; 2 n 2 2 12 . n er 0, 1 eller 2; og Xg og X^ er like eller forskjellige og er hver hydrogen, alkyl, fenyl eller substituert fenyl, eller Xc er hydrogen og X_ er amino, substituert amino, acylamino eller alkoksy, eller Xb , og X_ /sammen med det nitrogenatom som de er knyttet til, danner en 4-, 5-, 6- eller 7-leddet heterocyklus, karakterisert ved at et korresponderende 3-laktam med en hydroksygruppe i 1-stillingen, behandles med en aktivert form av en forbindelse med formelen for å danne sluttproduktene, idet beskyttelsesgruppen, dersom aminosubstituenten i "Vstillingen er beskyttet, eventuelt fjernes slik at det dannes et produkt med en aminosubstituent i" Wstillingen som eventuelt acyleres slik at en acylaminosubstituent i \ x-stillingen oppnås.-S-X2 , or -0-X2 ; X2 is alkyl, substituted alkyl, phenyl, substituted phenyl, phenylalkyl, (substituted phenyl)alkyl, alkanoyl, phenylalkanoyl, (substituted phenyl)alkanoyl, phenylcarbonyl, (substituted phenyl)carbonyl or heteroarylcarbonyl; A is -CH=CH-, -(CH_) -, -CH -O-, -CH„ -NH-, or -CH -S-CH_; 2 n 2 2 12 . n is 0, 1 or 2; and Xg and X^ are the same or different and are each hydrogen, alkyl, phenyl or substituted phenyl, or Xc is hydrogen and X_ is amino, substituted amino, acylamino or alkoxy, or Xb , and X_ / together with the nitrogen atom that they are linked to, forms a 4-, 5-, 6- or 7-membered heterocycle, characterized by that a corresponding 3-lactam with a hydroxy group in the 1-position is treated with an activated form of a compound with the formula to form the final products, the protecting group, if the amino substituent in the "V-position is protected, is optionally removed so that a product with a amino substituent in the W-position which is optionally acylated so that an acylamino substituent in the \x-position is obtained. 2. Fremgangsmåte som angitt i krav 1, karakterisert ved at det fremstilles forbindelser hvor Rc og Rc begge er hydrogen. -> b2. Process as set forth in claim 1, characterized in that compounds are produced where Rc and Rc are both hydrogen. -> b 3. Fremgangsmåte som angitt i krav 1, karakterisert ved at det fremstilles forbindelser med formelen 3. Method as stated in claim 1, characterized in that compounds with the formula are prepared eller en ester eller et salt derav, hvor R.J er acyl eller hydrogen eller en amino- eller nitrogen-beskyttende gruppe; R2 er hydrogen eller metoksy; R^ og R^j er like eller forskjellige og er hver hydrogen, alkyl, alkenyl, alkynyl, cykloalkyl, fenyl, substituert fenyl eller en 4-, 5-, 6- eller 7-leddet heterocyklus, eller den ene av R^ og R^ er hydrogen og den annen er azido, halogenmetyl, dihalogenmetyl, trihalogenmetyl, alkoksykarbonyl, 2-fenyletenyl, 2-fenyletynyl, -CH_X , karboksyl, - S- X^ t -0-X_, or an ester or salt thereof, wherein R.J is acyl or hydrogen or an amino or nitrogen protecting group; R 2 is hydrogen or methoxy; R 1 and R 2 are the same or different and are each hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, substituted phenyl or a 4-, 5-, 6- or 7-membered heterocycle, or one of R 2 and R^ is hydrogen and the other is azido, halomethyl, dihalomethyl, trihalomethyl, alkoxycarbonyl, 2-phenylethenyl, 2-phenylethynyl, -CH_X , carboxyl, - S- X^ t -0-X_, hvor X^ er azido,amino, hydroksy, alkanoylamino, fenylkarbonylamino, (substituert fenyl)karbonylamino, alkylsulfonyloksy, fenylsulfonyloksy, (substituert fenyl)sulfonyloksy, fenyl, substituert fenyl, cyano, where X^ is azido, amino, hydroxy, alkanoylamino, phenylcarbonylamino, (substituted phenyl)carbonylamino, alkylsulfonyloxy, phenylsulfonyloxy, (substituted phenyl)sulfonyloxy, phenyl, substituted phenyl, cyano, -S-X2 eller -0-X,,; X2 er alkyl, substituert alkyl, fenyl, substituert fenyl, fenylalkyl, (substituert fenyl)alkyl, alkanoyl, fenylalkanoyl, (substituert fenyl)-alkanoyl, fenylkarbonyl, (substituert fenyl)-karbonyl eller heteroarylkarbonyl; en av X^ og X^ er hydrogen og den annen er hydrogen eller alkyl, eller X^ og X^ sammen med det karbonatom som de er knyttet til, danner en cykloalkylgruppe; X,, er formyl, alkanoyl, fenylkarbonyl, (substituert fenyl)karbonyl, fenyl-alkylkarbonyl, (substituert fenyl)alkylkarbonyl, karboksyl, alkoksykarbonyl, aminokarbonyl, (substituert amino)karbonyl eller cyano;A er -CH=CH-, "(CH^-, -CH2" 0-, -CH2~ NH- eller-CH2 -S-CH2 ; n er 0, 1 eller 2 og X& og X7 er like eller forskjellige og er hver hydrogen, alkyl, fenyl eller substituert fenyl, eller Xg er hydrogen og X^ amino, substituert amino, acylamino eller alkoksy, eller Xc b og X_/, sammen med det nitrogenatom som de er knyttet til, danner en 4-, 5-, 6- eller 7-leddet heterocyklus; Ri- og Rg er like eller forskjellige og er hver hydrogen, alkyl, alkenyl, alkynyl, fenyl, substituert fenyl, cykloalkyl eller en 4-, 5-, 6- eller 7-leddet heterocyklus, eller R,- og Rg sammen med det karbonatom som de er knyttet til, utgjør cykloalkyl eller en 4-, 5-, 6- eller 7-leddet heterocyklus, eller en av R^ og Rg er hydrogen og den annen azido, halogenmetyl, dihalogenmetyl, trihalogenmetyl, halogen, alkoksykarbonyl, alkenyl, alkynyl, 2-fenyletenyl, 2-fenyletynyl, karboksyl, -CH2~ X1 , -S-X2 , -0-X2 , eller -S-X2 or -0-X,,; X2 is alkyl, substituted alkyl, phenyl, substituted phenyl, phenylalkyl, (substituted phenyl)alkyl, alkanoyl, phenylalkanoyl, (substituted phenyl)alkanoyl, phenylcarbonyl, (substituted phenyl)carbonyl or heteroarylcarbonyl; one of X^ and X^ is hydrogen and the other is hydrogen or alkyl, or X^ and X^ together with the carbon atom to which they are attached form a cycloalkyl group; X,, is formyl, alkanoyl, phenylcarbonyl, (substituted phenyl)carbonyl, phenyl-alkylcarbonyl, (substituted phenyl)alkylcarbonyl, carboxyl, alkoxycarbonyl, aminocarbonyl, (substituted amino)carbonyl or cyano; A is -CH=CH-, "( CH^-, -CH2" 0-, -CH2~ NH- or -CH2 -S-CH2 ; n is 0, 1 or 2 and X& and X7 are the same or different and are each hydrogen, alkyl, phenyl or substituted phenyl, or Xg is hydrogen and X^ amino, substituted amino, acylamino or alkoxy, or Xc b and X_/, together with the nitrogen atom to which they are attached, form a 4-, 5-, 6- or 7-membered heterocycle; R1 and Rg are the same or different and are each hydrogen, alkyl, alkenyl, alkynyl, phenyl, substituted phenyl, cycloalkyl or a 4-, 5-, 6- or 7-membered heterocycle, or R1- and Rg together with the carbon atom to which they are attached constitutes cycloalkyl or a 4-, 5-, 6- or 7-membered heterocycle, or one of R^ and Rg is hydrogen and the other azido, halomethyl, dihalomethyl, trihalomethyl, halogen, alkoxycarbonyl, alkenyl , alkynyl, 2-phenylethenyl, 2-phenylethynyl, carboxyl, -CH2~ X1 , -S-X2 , -O-X2 , or 4. Fremgangsmåte som angitt i krav 3, karakterisert ved at det fremstilles forbindelser hvor R2 er hydrogen. 4. Method as set forth in claim 3, characterized in that compounds are produced where R2 is hydrogen. 5. Fremgangsmåte som angitt i krav 4, karakterisert ved at det fremstilles forbindelser hvor en av R^ og R^ er hydrogen og den annen er hydrogen eller metyl.5. Process as stated in claim 4, characterized in that compounds are prepared where one of R^ and R^ is hydrogen and the other is hydrogen or methyl. 6. Fremgangsmåte som angitt i krav 4, karakterisert ved at det fremstilles forbindelser hvor R,, og R^ hver er hydrogen eller metyl.6. Process as set forth in claim 4, characterized in that compounds are prepared where R,, and R^ are each hydrogen or methyl. 7. Fremgangsmåte som angitt i krav 4, karakterisert ved at det fremstilles forbindelser hvor R^ er (Z)-[(2-amino-4-tiazolyl)(metoksyimino) acetyl].7. Process as stated in claim 4, characterized in that compounds are prepared where R 1 is (Z)-[(2-amino-4-thiazolyl)(methoxyimino) acetyl]. 8. Fremgangsmåte som angitt i krav 3, karakterisert ved at det fremstilles forbindelser hvor R^ er 8. Process as set forth in claim 3, characterized in that compounds are prepared where R^ is og R^ er metyl, etyl, karboksymetyl, 1-karboksy-1-metyletyl, 2,2,2-trifluoretyl eller 1-karboksycyklopropyl, fortrinnsvis metyl.and R 1 is methyl, ethyl, carboxymethyl, 1-carboxy-1-methylethyl, 2,2,2-trifluoroethyl or 1-carboxycyclopropyl, preferably methyl. 9. Fremgangsmåte som angitt i krav 3, for fremstilling av [3S-[3a(Z),43]]-[[3-[[(2-amino-4-tiazolyl)(metoksyimino)-acetyl]amino]-4-mety1-2-okso-1-azetidinyl]oksy]eddiksyre eller en ester eller et salt derav, fortrinnsvis en alkoksy-karbonylalkylester, spesielt [3S-[3a(Z),43]]-[[[[3-[[(2-amino-4-tiazolyl)(metoksyimino)acetyl]amino]-4-metyl-2-okso-1-azetidinyl]oksy]acetyl]oksy]eddiksyre-1,1-dimetylester.9. Process as stated in claim 3, for the preparation of [3S-[3a(Z),43]]-[[3-[[(2-amino-4-thiazolyl)(methoxyimino)-acetyl]amino]-4 -methyl-2-oxo-1-azetidinyl]oxy]acetic acid or an ester or salt thereof, preferably an alkoxycarbonylalkyl ester, especially [3S-[3a(Z),43]]-[[[[3-[[ (2-Amino-4-thiazolyl)(methoxyimino)acetyl]amino]-4-methyl-2-oxo-1-azetidinyl]oxy]acetyl]oxy]acetic acid 1,1-dimethyl ester. 10. Fremgangsmåte som angitt i krav 3, karakterisert ved at det fremstilles forbindelser hvor R^ er acyl, hydrogen eller en amino- eller nitrogen-beskyttende gruppe.10. Method as set forth in claim 3, characterized in that compounds are prepared where R 1 is acyl, hydrogen or an amino or nitrogen protecting group.
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